Derivatives of piperidinyl-and piperazinyl-alkyl carbamates, preparation methods thereof and application of same in therapeutics

ABSTRACT

Compound corresponding to the general formula (I): 
                         
in which A=N or CR 2 ; R 2 =H, F, OH, CN, CF 3 , C 1-6 -alkyl, C 1-6 -alkoxy; n=2 or 3 and m=2 when A=N; n=1, 2 or 3 and m=1 or 2 when A=CR 2 ; B=covalent bond or C 1-8 -alkylene; R 1 =optionally substituted heteroaryl; R 3 =CHR 4 CONHR 5 ; R 4 =H or C 1-6 -alkyl; R 5 =H, C 1-6 -alkyl, C 3-7 -cycloalkyl, C 3-7 -cycloalkyl-C 1 –C 6 -alkylene; in the form of a base, an acid-addition salt, a hydrate or a solvate. Therapeutic uses thereof.

CROSS-REFERENCE

This application is a continuation of WO International Application No.PCT/FR 2004/001102, filed 6 May, 2004, which WO application claims thebenefit of priority of French Patent Application No. 03/05540, filed May7, 2003.

BACKGROUND OF THE INVENTION

The invention relates to piperidyl- and piperazinyl-alkylcarbamatederivatives and to the preparation and therapeutic application thereof.

SUMMARY OF THE INVENTION

The compounds of the invention correspond to the general formula (I):

in which

-   A represents a nitrogen atom or a group CR₂ in which R₂ represents a    hydrogen or fluorine atom or a hydroxyl, cyano, trifluoromethyl,    C₁–₆-alkyl or C₁–₆-alkoxy group;-   n represents an integer equal to 2 or 3 and m represents an integer    equal to 2 when A represents a nitrogen atom;-   n represents an integer equal to 1, 2 or 3 and m represents an    integer equal to 1 or 2 when A represents a group CR₂;-   B represents a covalent bond or a C₁–₈-alkylene group;-   R₁ represents a group chosen from phenyl, pyridyl, pyridazinyl,    pyrimidinyl, pyrazinyl, triazinyl, oxazolyl, isoxazolyl, thiazolyl,    isothiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl, triazolyl,    naphthyl, quinolyl, tetrahydroquinolyl, isoquinolyl,    tetrahydroisoquinolyl, phthalazinyl, quinazolinyl, quinoxalinyl,    naphthyridinyl, cinnolyl, imidazopyrimidinyl, thienopyrimidinyl,    benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl,    benzisoxazolyl, benzothiazolyl, benzisothiazolyl, indazolyl,    pyrrolopyridyl, furopyridyl, dihydrofuropyridyl, thienopyridyl,    dihydrothienopyridyl, imidazopyridyl, pyrazolopyridyl,    oxazolo-pyridyl, isoxazolopyridyl and thiazolopyridyl;-   the group R₁ optionally being substituted with one or more groups R′    and/or R″;-   R′ represents a halogen atom or a cyano, nitro, hydroxyl,    C₁–₆-alkyl, C₁–₆-alkoxy, C₁–₆-thioalkyl, C₁–₆-fluoroalkyl,    C₁–₆-fluoroalkoxy, C₁–₆-fluorothioalkyl, C₃–₇-cycloalkyl,    C₃–₇-cycloalkyl-C₁–₆-alkylene, azetidinyl, piperidyl, pyrrolidinyl,    morpholinyl, piperazinyl, azepinyl, NH₂, NHR₆, NR₆R₇, NR₆COR₇,    NR₆SO₂R₇, COR₆, CO₂R₆, SO₂R₆, SO₂NR₆R₇ or —O—(C₁–₆-alkylene)-O—    group;-   R″ represents a phenyl, imidazolyl, pyridyl, pyridazinyl, pyrazinyl    or pyrimidinyl;-   the group(s) R″ being optionally substituted with one or more groups    R′, which may be identical to or different from each other;-   R₃ represents a group of general formula CHR₄CONHR₅ in which-   R₄ represents a hydrogen atom or a C₁–₆-alkyl group and-   R₅ represents a hydrogen atom or a C₁–₆-alkyl, C₃–₇-cycloalkyl or    C₃–₇-cycloalkyl-C₁–₆-alkylene group;-   R₆ and R₇ represent, independently of each other, a C₁–₆-alkyl    group.

DETAILED DESCRIPTION

Among the compounds of general formula (I), a first subgroup ofcompounds consists of compounds for which:

-   A represents a nitrogen atom; and/or-   n represents an integer equal to 2 or 3 and m represents an integer    equal to 2; and/or-   B represents a C₁–₈-alkylene group, more particularly an ethyl or    propyl; and/or-   R₁ represents a group chosen from phenyl, pyridyl, pyrimidinyl,    thiadiazolyl and naphthyl;-   the group R₁ being optionally substituted with one or more groups R′    and/or R″; and/or-   R′ represents a halogen atom, more particularly a chlorine, or a    nitro or C₁–₆-fluoroalkyl group, more particularly a    trifluoromethyl; and/or-   R″ represents a phenyl optionally substituted with one or more    groups, which may be identical to or different from each other,    chosen from a halogen atom, more particularly a chlorine, and a    cyano, C₁–₆-alkoxy, more particularly a methoxy, or    C₁–₆-fluoroalkoxy, more particularly a trifluoromethoxy, group;    and/or-   R₃ represents a group of general formula CHR₄CONHR₅ in which-   R₄ represents a hydrogen atom and-   R₅ represents a hydrogen atom or a C₁–₆-alkyl group, more    particularly a methyl or an ethyl, a C₃–₇-cycloalkyl group, more    particularly a cyclopropyl, or a C₃–₇-cycloalkyl-C₁–₆-alkylene    group, more particularly a cyclopropyl-methylene.

Among the compounds of general formula (I), a second subgroup ofcompounds consists of compounds for which:

-   A represents a group CR₂ in which R₂ represents a hydrogen or    fluorine atom or a hydroxyl group; and/or-   m represents an integer equal to 1 or 2 and n represents an integer    equal to 1 or 2; and/or-   B represents a covalent bond or a C₁–₄-alkylene group, more    particularly a methyl, ethyl or n-propyl; and/or-   R₁ represents a group chosen from phenyl, pyridyl, pyridazinyl,    pyrimidinyl, pyrazinyl, thiazolyl, quinolyl, isoquinolyl,    phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl,    furopyridyl, thienopyrimidinyl, imidazopyrimidinyl, benzothiazolyl,    benzimidazolyl and benzoxazolyl;-   the group R₁ being optionally substituted with one or more groups R′    and/or R″; and/or-   R′ represents a halogen atom, more particularly a fluorine, a    chlorine or a bromine, or a cyano group, C₁–₆-alkyl, more    particularly a methyl, ethyl, n-propyl or isobutyl, a C₁–₆-alkoxy,    more particularly a methoxy, C₁–₆-fluoroalkyl, more particularly a    trifluoromethyl, C₁–₆-fluoroalkoxy, more particularly a    trifluoromethoxy, C₃–₇-cycloalkyl, more particularly a cyclopropyl    or cyclopentyl, pyrrolidinyl, NH₂, NR₆R₇ or COR₆; and/or-   R″ represents a phenyl, imidazolyl or pyridyl; the group(s) R″ being    optionally substituted with one or more groups R′, which may be    identical to or different from each other, more particularly with    one or more chlorine or fluorine atoms; and/or-   R₃ represents a group of general formula CHR₄CONHR₅ in which-   R₄ represents a hydrogen atom or a C₁–₆-alkyl group, more    particularly a methyl, and-   R₅ represents a hydrogen atom or a C₁–₆-alkyl group, more    particularly a methyl or an ethyl, C₃–₇-cycloalkyl, more    particularly a cyclopropyl, C₃–₇-cycloalkyl-C₁–C₆-alkylene, more    particularly a cyclopropyl-methylene; and/or-   R₆ and R₇ represent, independently of each other, a C₁–₆-alkyl    group, more particularly a methyl.

Among the compounds of general formula (I), a third subgroup ofcompounds consists of compounds for which:

-   A represents a group CR₂ in which R₂ represents a hydrogen atom;    and/or-   m is equal to 2 and n is equal to 2; and/or-   B represents an ethyl group; and/or-   R₁ represents a group chosen from phenyl, pyridyl, pyridazinyl,    pyrimidinyl, pyrazinyl, thiazolyl, quinolyl, isoquinolyl,    phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl,    furopyridyl, thienopyrimidinyl, imidazopyrimidinyl, benzothiazolyl,    benzimidazolyl and benzoxazolyl;-   the group R₁ being optionally substituted with one or more groups R′    and/or R″; and/or-   R′ represents a halogen atom, more particularly a fluorine, a    chlorine or a bromine, or a cyano group, C₁–₆-alkyl, more    particularly a methyl, ethyl, n-propyl or isobutyl, a C₁–₆-alkoxy,    more particularly a methoxy, C₁–₆-fluoroalkyl, more particularly a    trifluoromethyl, C₁–₆-fluoroalkoxy, more particularly a    trifluoromethoxy, C₃–₇-cycloalkyl, more particularly a cyclopropyl    or cyclopentyl, pyrrolidinyl, NH₂, NR₆R₇ or COR₆; and/or-   R″ represents a phenyl, imidazolyl or pyridyl;-   the group(s) R″ being optionally substituted with one or more groups    R′, which may be identical to or different from each other, more    particularly with one or more chlorine or fluorine atoms; and/or-   R₃ represents a group of general formula CHR₄CONHR₅ in which-   R₄ represents a hydrogen atom and-   R₅ represents a hydrogen atom or a C₁–C₆-alkyl group, more    particularly a methyl or an ethyl; and/or-   R₆ and R₇ represent, independently of each other, a C₁–₆-alkyl    group, more particularly a methyl.

A subject of the invention is also, among the compounds of generalformula (I), compounds corresponding to the general formula (I′):

in which

-   A represents a nitrogen atom or a group CR₂ in which R₂ represents a    hydrogen or fluorine atom or a hydroxyl, cyano, trifluoromethyl,    C₁–₅-alkyl or C₁–₅-alkoxy group;-   n represents an integer equal to 2 or 3 and m represents an integer    equal to 2 when A represents a nitrogen atom;-   n represents an integer equal to 1, 2 or 3 and m represents an    integer equal to 1 or 2 when A represents a group CR₂;-   B represents a covalent bond or a C₁–₈-alkylene group;-   R₁ represents a group chosen from phenyl, pyridyl, pyridazinyl,    pyrimidinyl, pyrazinyl, triazinyl, thiazolyl, imidazolyl,    oxadiazolyl, thiadiazolyl, triazolyl, naphthyl, quinolyl,    tetrahydroquinolyl, isoquinolyl, tetrahydroisoquinolyl,    phthalazinyl, quinazolinyl, quinoxalinyl, naphthyridinyl, cinnolyl,    imidazopyrimidinyl, thienopyrimidinyl, benzofuranyl, benzothienyl,    benzimidazolyl, benzoxazolyl, benzisoxazolyl, benzothiazolyl,    benzisothiazolyl, indazolyl, pyrrolopyridyl, furopyridyl,    dihydrofuropyridyl, thienopyridyl, dihydrothienopyridyl,    imidazopyridyl, pyrazolopyridyl, oxazolopyridyl, isoxazolopyridyl    and thiazolopyridyl;-   optionally substituted with one or more substituents chosen from a    halogen atom and a cyano, nitro, C₁–₅-alkyl, C₁–₃-alkoxy,    C₁–₅-thioalkyl, C₁–₅-fluoroalkyl, C₁–₃-fluoroalkoxy,    C₁–₃-fluorothioalkyl, C₃–₅-cycloalkyl,    C₃–₅-cycloalkyl-C₁–₃-alkylene, piperidyl, pyrrolidinyl, morpholinyl,    NH₂, NHR₆, NR₆R₇, NHCOR₆, COR₆, CO₂R₆, SO₂R₆, —O—(C₁–₃-alkylene)-O—,    phenyl, pyridyl or pyrimidinyl group;-   the phenyl, pyridyl and pyrimidinyl groups possibly being    substituted with one or more substituents chosen from a halogen atom    and a cyano, nitro, hydroxyl, C₁–₅-alkyl, C₁–₃-alkoxy,    C₁–₅-thioalkyl, C₁–₅-fluoroalkyl, C₁–₃-fluoroalkoxy,    C₁–₃-fluorothioalkyl, C₃–₅-cycloalkyl,    C₃–₅-cycloalkyl-C₁–₃-alkylene, piperidyl, pyrrolidinyl, morpholinyl,    NH₂, NHR₆, NR₆R₇, NHCOR₆, COR₆, CO₂R₆, SO₂R₆, or    —O—(C₁–₃-alkylene)-O— group;-   R₃ represents a group of general formula CHR₄CONHR₅ in which-   R₄ represents a hydrogen atom or a C₁–₃-alkyl group and-   R₅ represents a hydrogen atom or a C₁–₃-alkyl, C₃–₅-cycloalkyl or    C₃–₅-cycloalkyl-C₁–₃-alkylene group;-   R₆ and R₇ represent, independently of each other, a C₁–₃-alkyl    group.

The compounds of general formula (I) may comprise one or more asymmetriccarbons. They may exist in the form of enantiomers or diastereoisomers.These enantiomers and diastereoisomers, and also mixtures thereof,including racemic mixtures, form part of the invention.

The compounds of general formula (I) may exist in the form of bases orof acid-addition salts. Such addition salts form part of the invention.

These salts are advantageously prepared with pharmaceutically acceptableacids, but the salts of other acids that are useful, for example, forthe purification or isolation of the compounds of formula (I) also formpart of the invention.

The compounds of general formula (I) may be in the form of hydrates orsolvates, i.e. in the form of associations or combinations with one ormore water molecules or with a solvent. Such hydrates and solvates alsoform part of the invention.

In the context of the invention, the following definitions apply:

-   C_(t-z) in which t and z may take values from 1 to 8, a carbon-based    chain possibly containing from t to z carbon atoms, for example a    C₁–₃ carbon-based chain which may contain from 1 to 3 carbon atoms,-   alkyl, a saturated, linear or branched aliphatic group, for example    a C₁–₃-alkyl group represents a linear or branched carbon-based    chain of 1 to 3 carbon atoms, more particularly a methyl, ethyl,    propyl or 1-methylethyl,-   alkylene, a saturated, linear or branched divalent alkyl group, for    example a C₁–₃-alkylene group represents a linear or branched    divalent carbon-based chain of 1 to 3 carbon atoms, more    particularly a methylene, ethylene, 1-methylethylene or propylene,-   cycloalkyl, a cyclic alkyl group, for example a C₃–₅-cycloalkyl    group represents a cyclic carbon-based group of 3 to 5 carbon atoms,    more particularly a cyclopropyl, cyclobutyl or cyclopentyl,-   alkoxy, an —O-alkyl group containing a saturated, linear or branched    aliphatic chain,-   thioalkyl, an —S-alkyl group containing a saturated, linear or    branched aliphatic chain,-   fluoroalkyl, an alkyl group in which one or more hydrogen atoms have    been replaced with a fluorine atom,-   fluoroalkoxy, an alkoxy group in which one or more hydrogen atoms    have been replaced with a fluorine atom,-   fluorothioalkyl, a thioalkyl group in which one or more hydrogen    atoms have been replaced with a fluorine atom,-   halogen atom, a fluorine, a chlorine, a bromine or an iodine.

The compounds of the invention may be prepared according to variousmethods, illustrated by the schemes that follow.

Thus, a first method (Scheme 1) consists in reacting an amine of generalformula (II), in which A, B, R₁, n and m are as defined above, with acarbonate of general formula (IIIa) in which Z represents a hydrogenatom or a nitro group, R₄ is as defined above and R represents a methylor ethyl group. The carbamate ester of general formula (Ia) thusobtained is then converted into a compound of general formula (I), viaaminolysis using an amine of general formula R₅NH₂ in which R₅ is asdefined above. The aminolysis reaction may be performed in a solventsuch as methanol or a mixture of solvents such as methanol andtetrahydrofuran or methanol and dioxane.

One variant for obtaining the compounds of general formula (I)(Scheme 1) consists in reacting an amine of general formula (II), asdefined above, with a carbonate of general formula (IIIb), in which Zrepresents a hydrogen atom or a nitro group and R₄ and R₅ are as definedabove, in a solvent such as toluene or dichloroethane, at a temperatureof between 0° C. and 80° C.

The carbonates of general formula (IIIa) and (IIIb) may be preparedaccording to any method described in the literature, for example byreacting an alcohol of general formula HOCHR₄COOR, in which R representsa methyl or ethyl group, or HOCHR₄CONHR₅ in which R₄ and R₅ are asdefined above, with phenyl chloroformate or 4-nitrophenyl chloroformate,in the presence of a base such as triethylamine ordiisopropylethylamine.

A second method for obtaining the compounds of general formula (I)(Scheme 2) consists in reacting a derivative of general formula (IIa) inwhich Y represents a hydroxyl, mesylate or tosylate group or a chlorine,bromine or iodine atom and A, B, R₁, n and m are as defined above, withan oxazolidinedione of general formula (IV) in which R₄ is as definedabove, to give the oxazolidinedione derivative of general formula (V).In the case where Y represents a hydroxyl group, the reaction may beperformed according to the Mitsunobu conditions (Synthesis, 1981, 1–28),for example via the action of diethyl or diisopropyl azodicarboxylate inthe presence of triphenylphosphine. In the case where Y represents achlorine, bromine or iodine atom or a mesylate or tosylate group, thereaction may be performed in the presence of a base such as1,1,3,3-tetramethylguanidine, sodium hydride or sodium tert-butoxide ina solvent such as tetrahydrofuran, acetonitrile or dimethylformamide, ata temperature of between 0° C. and the reflux temperature of thesolvent. The oxazolidinedione derivative of general formula (V) thusobtained is then converted into a compound of general formula (I), viaaminolysis using an amine of general formula R₅NH₂ in which R₅ is asdefined above.

The compounds of general formulae (I), (Ia), (II), (IIa) and (V), inwhich R₁ is substituted with a group R″, may also be prepared byreacting the corresponding compounds of general formulae (I), (Ia),(II), (IIa) and (V), for which R₁ is substituted with a chlorine,bromine or iodine atom or with a triflate group in the position intowhich the group R″ is to be introduced, with an aryl- orheteroaryl-boronic acid derivative according to the Suzuki reactionconditions (Chem. Rev. 1995, 95, 2457–2483) or with an aryl- orheteroaryl-trialkylstannane derivative according to the Stille reactionconditions (Angew. Chem. Int. Ed. 1986, 25, 504–524).

The compounds of general formulae (II), (IIIa) and (IV), when theirpreparation method is not described, are commercially available or aredescribed in the literature, or alternatively may be prepared accordingto methods that are described therein or known to those skilled in theart.

The amines of general formula R₅NH₂ are commercially available.

According to another of its aspects, a subject of the invention is alsothe compounds of formula (Ia) in which n, m, A, B, R₁ and R₄ are asdefined above and R represents a methyl or ethyl group. The compounds offormula (Ia) are useful as synthetic intermediates for the preparationof the compounds of formula (I).

According to another of its aspects, a subject of the invention is alsothe compounds of formula (V) in which n, m, A, B, R₁ and R₄ are asdefined above, the following compounds being excluded:

-   *3-[1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-piperidyl]-2,4-oxazolidinedione-   *3-[1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-piperidyl]-5-methyl-2,4-oxazolidinedione-   *3-[1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-piperidyl]-5-ethyl-2,4-oxazolidinedione-   *3-[1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-piperidyl]-5-propyl-2,4-oxazolidinedione-   *3-[1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-piperidyl]-5-(1-methylethyl)-2,4-oxazolidinedione.

The compounds of formula (V) are useful as synthetic intermediates forthe preparation of the compounds of formula (I).

The examples that follow illustrate the preparation of a number ofcompounds of the invention. These examples are not limiting and aregiven merely to illustrate the invention. The microanalyses and the IR,NMR and/or LC/MS (Liquid Chromatography coupled to Mass Spectroscopy)spectra confirm the structures and purities of the compounds obtained.

m.p. (° C.) represents the melting point in degrees Celsius.

The numbers indicated in parentheses in the example titles correspond tothose in the first column of the table hereinbelow.

The IUPAC (International Union of Pure and Applied Chemistry)nomenclature has been used for the naming of the compounds in theexamples that follow.

EXAMPLE 1 (COMPOUND 38) 2-(Methylamino)-2-oxoethyl2-[4-(1-naphthyl)-1-piperazinyl]ethylcarbamate hydrochloride

1.1.2-{2-[4-(1-Naphthyl)-1-piperazinyl]ethyl}-1H-isoindole-1,3(2H)-dione

A suspension of 1.17 g (5.52 mmol) of 1-(1-naphthyl)piperazine(Tetrahedron Letters, 1998, 39(15), 2219–2222), 0.99 g (7.15 mol) ofpotassium carbonate and 1.68 g (6.62 mmol) of2-(2-bromoethyl)-1H-isoindole-1,3(2H)-dione in 15 ml ofN,N-dimethylformamide is heated at 90° C. for 2 hours.

The mixture is allowed to cool to room temperature and is concentratedunder reduced pressure. The residue is taken up in ethyl acetate andwater, the aqueous phase is separated out and extracted three times withethyl acetate, and the combined organic phases are washed with saturatedaqueous sodium chloride solution and dried over sodium sulfate. Afterevaporating off the solvent, the residue obtained is purified bychromatography on silica gel, eluting with a 40/60 mixture of ethylacetate and cyclohexane.

1.14 g of pure product are thus obtained in the form of an oil.

1.2. 2-[4-(1-Naphthyl)-1-piperazinyl]ethanamine

0.17 ml (3.55 mmol) of hydrazine monohydrate is added slowly at roomtemperature to a solution of 1.14 g (2.96 mmol) of2-{2-[4-(1-naphthyl)-1-piperazinyl]ethyl}-1H-isoindole-1,3(2H)-dione,prepared in step 1.1, in 15 ml of ethanol. The reaction mixture is thenrefluxed for 1 hour.

The mixture is allowed to cool to room temperature, the insolublematerial is separated out by filtration and the filtrate is concentratedunder reduced pressure. The residue is taken up in 20 ml of ether andstirred at room temperature for 20 minutes. The insoluble material isagain separated out and the filtrate is concentrated under reducedpressure. The residue obtained is purified by chromatography on silicagel, eluting with a 90/10/1 mixture of dichloromethane, methanol and 28%aqueous ammonia.

0.45 g of amine is thus obtained in the form of a colourless oil.

1.3. Ethyl[(phenyloxycarbonyl)oxy]acetate

32 ml (256 mmol) of phenyl chloroformate are added slowly at roomtemperature to a solution of 25 g (240 mmol) of ethyl glycolate and 55ml (315 mmol) of diisopropylethylamine in 500 ml of toluene. Stirring iscontinued at room temperature for 2 hours.

The salt formed is separated out and the filtrate is concentrated underreduced pressure.

53.7 g of oily product are obtained, and are used without furtherpurification in the following step.

1.4.Ethyl[({2,4-(1-naphthyl)-1-piperazinyl]ethyl}amino)carbonyl]oxyacetate

A solution of 0.45 g (1.76 mmol) of2-[4-(1-naphthyl)-1-piperazinyl]ethanamine, prepared in step 1.2, and0.48 g (2.16 mmol) of ethyl [(phenyloxycarbonyl)oxy]acetate, obtained instep 1.3, in 15 ml of toluene is heated at 50° C. for 6 hours.

The mixture is allowed to cool to room temperature, the insolublematerial is separated out by filtration and the filtrate is concentratedunder reduced pressure. The residue is taken up in dichloromethane andwater, the aqueous phase is separated out and extracted three times withdichloromethane, and the combined organic phases are washed withsaturated aqueous sodium chloride solution and dried over sodiumsulfate. After evaporating off the solvent, the residue obtained ispurified by chromatography on silica gel, eluting with a 97/3 and then93/7 mixture of dichloromethane and methanol. 0.49 g of pure product isthus obtained in the form of an oil.

1.5. 2-(Methylamino)-2-oxoethyl2-[4-(1-naphthyl)-1-piperazinyl]ethylcarbamate

1.9 ml (3.75 mmol) of a solution (2M) of methylamine in tetrahydrofuranare added to a solution of 0.48 g (1.25 mmol) ofethyl[({2,4-(1-naphthyl)-1-piperazinyl]ethyl}amino)carbonyl]oxyacetate,prepared in step 1.4, in 5 ml of methanol. Stirring is continued at roomtemperature for 1 hour.

After concentrating under reduced pressure, the residue obtained ispurified by chromatography on silica gel, eluting with a 97/3 mixture ofdichloromethane and methanol. An oily residue is obtained, which istaken up with a solution of hydrochloric acid (5N) in isopropanol. Themixture is concentrated to dryness and the salt obtained is thenrecrystallized from a 1/1 mixture of acetone and diisopropyl ether.

0.23 g of pure monohydrochloride product is thus obtained in the form ofa white solid.

LC-MS: M+H=371 m.p. (° C.): 166° C. ¹H NMR (DMSO) δ (ppm): 2.55 (d, 3H);3.20–3.75 (unresolved peak, 12H); 4.40 (s, 2H); 7.10 (d, 1H); 7.35–7.70(unresolved peak, 4H); 7.80–8.05 (unresolved peak, 2H); 8.15 (dd, 1H);10.90 (broad s, 1H).

EXAMPLE 2 (COMPOUND 157) 2-(Methylamino)-2-oxoethyl3-[1-(1-isoquinolyl)-4-piperidyl]propylcarbamate hydrochloride

2.1. 2-[1-(1-Isoquinolyl)-4-piperidyl]ethanol

4.17 g (25.50 mmol) of 1-chloroisoquinoline, 3.62 g (28 mmol) of2-(4-piperidyl)ethanol, 5.90 g (61.20 mmol) of sodium tert-butoxide and0.476 g (0.765 mmol) of BINAP(2,2′-bis(diphenylphosphino)-1,1′-binaphthyl) suspended in 50 ml oftoluene are introduced under an inert atmosphere. 0.233 g (0.255 mmol)of tris(dibenzylideneacetone)dipalladium is then added. The reactionmixture is then refluxed for 12 hours.

The salts are separated out by filtration through Celite and thefiltrate is then concentrated under reduced pressure. The residue istaken up in ethyl acetate and water, the aqueous phase is separated outand extracted twice with ethyl acetate, and the combined organic phasesare washed with saturated aqueous sodium chloride solution and driedover sodium sulfate. After evaporating off the solvent, the residueobtained is purified by chromatography on silica gel, eluting with a97/3 mixture of dichloromethane and methanol.

3.34 g of product are obtained in the form of a grey paste.

2.2. 1-[4-(2-Chloroethyl)-1-piperidyl]isoquinoline

2.20 ml (30.10 mmol) of thionyl chloride are added dropwise to asolution of 3.09 g (12.10 mmol) of2-[1-(1-isoquinolyl)-4-piperidyl]ethanol, prepared in step 2.1, in 30 mlof dichloromethane. The reaction mixture is then refluxed for 5 hours.

The mixture is concentrated to dryness under reduced pressure. Theresidue is taken up in 40 ml of dichloromethane and 30 ml of aqueoussodium hydroxide solution (1M). The aqueous phase is separated out andextracted twice with dichloromethane, the combined organic phases arewashed with saturated aqueous sodium chloride solution and dried oversodium sulfate, and the filtrate is concentrated under reduced pressure.2.70 g of product are obtained in the form of a brown paste, which isused without further purification in the following step.

2.3. 3-[1-(1-Isoquinolyl)-4-piperidyl]propanenitrile

0.63 g (9.57 mmol) of potassium cyanide is added portionwise to asuspension of 2.63 g (9.57 mmol) of1-[4-(2-chloroethyl)-1-piperidyl]isoquinoline, prepared in step 2.2, and0.048 g (0.29 mmol) of potassium iodide in 30 ml of dimethyl sulfoxide.The reaction mixture is maintained at about 120° C. for 16 hours. Themixture is allowed to cool to room temperature and 90 ml of water andethyl acetate are then added. The aqueous phase is separated out andextracted three times with ethyl acetate, the combined organic phasesare washed with saturated aqueous sodium chloride solution and driedover sodium sulfate, and the filtrate is concentrated under reducedpressure. The residue thus obtained is purified by chromatography onsilica gel, eluting with a 30/70 mixture of ethyl acetate andcyclohexane.

0.77 g of product is obtained in the form of a yellow solid.

m.p. (° C.): 141–143° C.

2.4. 3-[1-(1-Isoquinolyl)-4-piperidyl]propanamine

A solution of 0.77 g (2.90 mmol) of3-[1-(1-isoquinolyl)-4-piperidyl]propanenitrile, prepared in step 2.3,in 16 ml of tetrahydrofuran is added dropwise to a suspension of 0.22 g(5.80 mmol) of lithium aluminium hydride in 8 ml of tetrahydrofuran. Thereaction mixture is then refluxed for 5 hours.

The reaction medium is cooled to about 0° C. and 15 ml of aqueous sodiumhydroxide solution (1M) are then added slowly. The mixture is stirred atroom temperature for 30 minutes, followed by portionwise addition of wetsodium sulfate. The salts are separated out by filtration through paperand the phases are then allowed to separate by settling. The aqueousphase is extracted three times with ethyl acetate, the combined organicphases are dried over sodium sulfate and the filtrate is concentratedunder reduced pressure. The residue thus obtained is purified bychromatography on silica gel, eluting with a 93/7/0.7 mixture ofdichloromethane, methanol and 28% aqueous ammonia.

0.329 g of product is obtained in the form of a yellow oil thatcrystallizes at room temperature.

2.5.Ethyl[{3-[1-(1-isoquinolyl)-4-piperidyl]propyl}amino)carbonyl]oxyacetate

The process is performed as in Example 1 (step 1.4). Starting with 0.350g (1.30 mmol) of 3-[1-(1-isoquinolyl)-4-piperidyl]propanamine, obtainedin step 2.4, and 0.32 g (1.43 mmol) ofethyl[(phenyloxycarbonyl)oxy]acetate, prepared in step 1.3 of Example 1,and after chromatography on silica gel, eluting with a 20/80 and then30/70 mixture of ethyl acetate and cyclohexane, 0.383 g of product isobtained in the form of a yellow paste.

2.6. 2-(Methylamino)-2-oxoethyl3-[1-(1-isoquinolyl)-4-piperidyl]propylcarbamate

The process is performed as described in Example 1 (step 1.5). Startingwith 0.380 g (0.95 mmol) ofethyl[{3-[1-(1-isoquinolyl)-4-piperidyl]propyl}-amino)carbonyl]oxyacetate,obtained in step 2.5, and 4.8 ml (9.51 mmol) of a solution (2M) ofmethylamine in tetrahydrofuran, and after chromatography on silica gel,eluting with a 98/2 and then 95/5 mixture of dichloromethane andmethanol, 0.277 g of product is obtained in the form of an oil. Thisoily residue is then taken up in a solution of hydrochloric acid (5N) inisopropanol and the salt formed is filtered off and then washed withethyl acetate.

After drying under vacuum at about 40° C., 0.204 g of hydrochloride isobtained in the form of an amorphous white solid.

LC-MS: M+H=385 ¹H NMR (DMSO+D₂O) δ (ppm): 1.30 (m, 2H); 1.40–1.80(unresolved peak, 5H); 1.90 (broad d, 2H); 2.60 (s, 3H); 3.05 (m, 2H);3.40 (t, 2H); 4.05 (broad d, 2H); 4.30 (s, 2H); 7.50 (d, 1H); 7.80 (m,2H); 7.95 (t, 1H); 8.05 (d, 1H); 8.20 (d, 1H).

EXAMPLE 3 (COMPOUND 44) 2-Amino-2-oxoethyl2-{1-[3-(trifluoromethyl)phenyl]-4-piperidyl}ethylcarbamate

3.1. 2-{1-[3-(Trifluoromethyl)phenyl]-4-piperidyl}ethanol

The process is performed as described in Example 2 (step 2.1). Startingwith 25.6 g (113.90 mmol) of 1-bromo-3-(trifluoromethyl)benzene, 17.66 g(136.60 mmol) of 2-(4-piperidyl)ethanol, 26.24 g (273 mmol) of sodiumtert-butoxide, 2.12 g (3.41 mmol) of BINAP and 1.04 g (1.14 mmol) oftris-(dibenzylideneacetone)dipalladium, and after chromatography onsilica gel, eluting with a 25/75 mixture of ethyl acetate andcyclohexane, 17.90 g of an orange-coloured oily residue are obtained.This residue is then taken up in 100 ml of methanol, a solution of 4.24g of potassium hydroxide in 15 ml of methanol is then added and stirringis continued at room temperature for 1 hour. The mixture is concentratedunder reduced pressure and the residue is then taken up in chloroformand aqueous hydrochloric acid solution (1N). The organic phase isseparated out and dried over sodium sulfate, and the filtrate isconcentrated under reduced pressure. 14 g of product are obtained in theform of a dark yellow oil, which is used without further purification inthe following step.

3.2. 2-{1-[3-(Trifluoromethyl)phenyl]-4-piperidyl}ethyl methanesulfonate

A solution of 1 g (8.78 mmol) of mesyl chloride in 5 ml ofdichloromethane is added dropwise under an inert atmosphere to asolution of 2 g (7.32 mmol) of2-{1-[3-(trifluoromethyl)phenyl]-4-piperidyl}ethanol, obtained in step3.1, and 1.53 ml (10.98 mmol) of triethylamine in 40 ml ofdichloromethane, cooled to about 0° C. Stirring is continued at 0° C.for 1 hour and then at room temperature for 2 hours.

Water is added to the reaction medium, the aqueous phase is separatedout and extracted three times with dichloromethane, the combined organicphases are washed with saturated aqueous sodium chloride solution anddried over sodium sulfate, and the filtrate is concentrated underreduced pressure.

2.5 g of product are thus obtained in the form of an oil, which is usedwithout further purification in the following step.

3.3.3-(2-{1-[3-(Trifluoromethyl)phenyl]-4-piperidyl}ethyl)-1,3-oxazolidine-2,4-dione

A solution of 2.3 g (6.545 mmol) of2-{1-[3-(trifluoromethyl)phenyl]-4-piperidyl}ethyl methanesulfonate,prepared in step 3.2, 0.694 g (6.87 mmol) of 1,3-oxazolidine-2,4-dione(J. Med. Chem., 1991, 34, 1538–1544) and 1.5 g (13.09 mmol) of1,1,3,3-tetramethylguanidine in 30 ml of tetrahydrofuran is refluxed for12 hours under an inert atmosphere.

The mixture is concentrated under reduced pressure. The residue is takenup in dichloromethane and water, the aqueous phase is separated out andextracted twice with dichloromethane, and the combined organic phasesare washed with saturated aqueous sodium chloride solution and driedover sodium sulfate. After evaporating off the solvent, the residueobtained is purified by chromatography on silica gel, eluting with a20/80 and then 40/60 mixture of ethyl acetate and cyclohexane.

1.61 g of pure product are obtained in the form of an oil.

3.4. 2-Amino-2-oxoethyl2-{1-[3-(trifluoromethyl)phenyl]-4-piperidyl}ethylcarbamate

9.3 ml (64.82 mmol) of a solution of aqueous ammonia (7N) in methanolare added to a solution of 0.77 g (2.16 mmol) of3-(2-{1-[3-(trifluoromethyl)-phenyl]-4-piperidyl}ethyl)-1,3-oxazolidine-2,4-dione,obtained in step 3.3, in 10 ml of a 1/1 mixture of methanol andtetrahydrofuran. Stirring is continued at room temperature for 24 hours.

After concentrating under reduced pressure, the residue obtained ispurified by chromatography on silica gel, eluting with a 97/3 and then95/5 mixture of dichloromethane and methanol, followed byrecrystallization from a mixture of ethyl acetate and diisopropyl ether.

0.370 g of pure product is obtained in the form of a white solid.

LC-MS: M+H=374 m.p. (° C.): 140–142° C. ¹H NMR (CDCl₃) δ (ppm):1.30–1.55 (unresolved peak, 5H); 1.90 (broad d, 2H); 2.80 (t, 2H); 3.35(q, 2H); 3.80 (broad d, 2H); 4.60 (s, 2H); 4.90 (broad s, 1H); 5.55(broad s, 1H); 6.05 (broad s, 1H); 7.10 (m, 3H); 7.35 (t, 1H).

EXAMPLE 4 (COMPOUND 47) 2-(Methylamino)-2-oxoethyl2-[1-(6-methyl-2-pyridyl)-4-piperidyl]ethylcarbamate hydrochloride

4.1. 2-[1-(6-Methyl-2-pyridyl)-4-piperidyl]ethanol

1 g (7.74 mmol) of 2-(4-piperidyl)ethanol and 0.987 g (7.74 mmol) of2-chloro-6-methylpyridine are introduced into an autoclave. The mixtureis then heated at 130° C. for 17 hours.

The reaction mixture is allowed to cool to room temperature and is thentaken up in chloroform and saturated aqueous sodium hydrogen carbonatesolution. The aqueous phase is separated out and extracted twice withchloroform, the combined organic phases are washed with saturatedaqueous sodium chloride solution and dried over sodium sulfate, and thefiltrate is concentrated under reduced pressure.

1.21 g of product are thus obtained in the form of an orange-colouredliquid, which is used without further purification in the followingstep.

4.2. 2-[1-(6-Methyl-2-pyridyl)-4-piperidyl]ethyl methanesulfonate

The process is performed as in Example 3 (step 3.2). Starting with 0.661g (3 mmol) of 2-[1-(6-methyl-2-pyridyl)-4-piperidyl]ethanol, obtained instep 4.1, 0.378 g (3.30 mmol) of mesyl chloride and 0.63 ml (4.50 mmol)of triethylamine, 0.779 g of product is obtained in the form of anorange-coloured oil, which is used without further purification in thefollowing step.

4.3.3-{2-[1-(6-Methyl-2-pyridyl)-4-piperidyl]ethyl}-1,3-oxazolidine-2,4-dione

The process is performed according to the method described in Example 3(step 3.3). Starting with 0.776 g (2.60 mmol) of2-[1-(6-methyl-2-pyridyl)-4-piperidyl]ethyl methanesulfonate, obtainedin step 4.2, 0.315 g (3.12 mmol) of 1,3-oxazolidine-2,4-dione and 0.65ml (5.20 mmol) of 1,1,3,3-tetramethylguanidine, and after chromatographyon silica gel, eluting with a 30/70 mixture of ethyl acetate andcyclohexane, 0.76 g of pure product is obtained in the form of a yellowoil.

4.4. 2-(Methylamino)-2-oxoethyl2-[1-(6-methyl-2-pyridyl)-4-piperidyl]ethylcarbamate

The process is performed according to the procedure described in Example1 (step 1.5). Starting with 0.841 g (2.77 mmol) of3-{2-[1-(6-methyl-2-pyridyl)-4-piperidyl]ethyl}-1,3-oxazolidine-2,4-dione,obtained in step 4.3, and 6.9 ml (13.86 mmol) of a solution (2M) ofmethylamine in tetrahydrofuran, 0.598 g of pure product is obtained inthe form of an oil, after chromatography on silica gel, eluting with a95/5 mixture of dichloromethane and methanol. This oily residue is thentaken up with a solution of hydrochloric acid (5N) in isopropanol andthe salt formed is filtered off and then washed successively withacetone and then with ether.

After drying under vacuum at about 80° C., 0.492 g of hydrochloride isobtained in the form of a white powder.

LC-MS: M+H=335 m.p. (° C.): 95–100° C. ¹H NMR (DMSO+D₂O) δ (ppm):0.95–1.45 (unresolved peak, 4H); 1.60 (m, 1H); 1.80 (broad d, 2H); 2.40(s, 3H); 2.60 (s, 3H); 2.90–3.20 (unresolved peak, 4H); 4.10 (broad d,2H); 4.30 (s, 2H); 6.70 (d, 1H); 7.10 (d, 1H); 7.75 (dd, 1H).

EXAMPLE 5 (COMPOUND 154)

2-(Methylamino)-2-oxoethyl[1-(1-isoquinolyl)-4-piperidyl]methylcarbamatehydrochloride

5.1. [1-(1-Isoquinolyl)-4-piperidyl]methanol

The process is performed as described in Example 2 (step 2.1). Startingwith 2.50 g (15.28 mmol) of 1-chloroisoquinoline, 1.94 g (136.6 mmol) of4-piperidylmethanol, 3.53 g (36.67 mmol) of sodium tert-butoxide, 0.285g (0.46 mmol) of BINAP and 0.140 g (0.15 mmol) oftris(dibenzylideneacetone)dipalladium, and after chromatography onsilica gel, eluting with a 98/2/0.2 and then 95/5/0.5 mixture ofdichloromethane, methanol and 28% aqueous ammonia, 2.40 g of pureproduct are obtained in the form of a viscous orange oil.

5.2. 3-{[1-(1-Isoquinolyl)-4-piperidyl]methyl}-1,3-oxazolidine-2,4-dione

A solution of 2.01 g (9.95 mmol) of diisopropyl azodicarboxylate (DIAD)in 5 ml of tetrahydrofuran is added dropwise, under an inert atmosphere,to a solution of 2.4 g (9.95 mmol) of[1-(1-isoquinolyl)-4-piperidyl]methanol, prepared in step 5.1, 2.87 g(10.94 mmol) of triphenylphosphine and 1.21 g (11.93 mmol) of1,3-oxazolidine-2,4-dione in 40 ml of tetrahydrofuran, cooled to about−10° C., the temperature of the reaction medium being maintainedthroughout between −10° C. and 0° C. Stirring is then continued at 0° C.for 1 hour and then at 25° C. for 18 hours.

The mixture is concentrated under reduced pressure and the residue istaken up in dichloromethane and 10 ml of aqueous 5% sodium hydroxidesolution. The aqueous phase is separated out and then extracted twicewith dichloromethane. The organic phases are combined and washedsuccessively with aqueous hydrochloric acid solution (1N) and then withsaturated aqueous sodium hydrogen carbonate solution and with saturatedaqueous sodium chloride solution. The organic phase is dried over sodiumsulfate and the filtrate is concentrated under reduced pressure. Theresidue thus obtained is purified by chromatography on silica gel,eluting with a 99/1/0.1 and then 98/2/0.2 mixture of dichloromethane,methanol and 28% aqueous ammonia.

3.57 g of oxazolidinedione are thus obtained in the form of an orangepaste.

5.3.2-(Methylamino)-2-oxoethyl[1-(1-isoquinolyl)-4-piperidyl]methylcarbamate

The process is performed according to the procedure described in Example1 (step 1.5). Starting with 3.57 g (10.97 mmol) of3-{[1-(1-isoquinolyl)-4-piperidyl]methyl}-1,3-oxazolidine-2,4-dione,obtained in step 5.2, and 27 ml (54.86 mmol) of a solution (2M) ofmethylamine in tetrahydrofuran, and after chromatography on silica gel,eluting with a 95/5/0.5 mixture of dichloromethane, methanol and 28%aqueous ammonia, 0.90 g of pure product is obtained in the form of ayellow paste. This residue is then taken up in a solution ofhydrochloric acid (5N) in isopropanol, and the salt formed is filteredoff and then washed with acetone.

After drying under vacuum at about 80° C., 0.728 g of hydrochloride isobtained in the form of a pale yellow solid.

LC-MS: M+H=357 m.p. (° C.): 208–212° C. (decomposition) ¹H NMR (D₂O) δ(ppm): 1.55 (m, 2H); 1.95 (m, 3H); 2.70 (s, 3H); 3.20 (broad d, 2H);3.45 (t, 2H); 4.10 (broad d, 2H); 4.50 (s, 2H); 7.35 (d, 1H); 7.55 (d,1H); 7.70 (m, 1H); 7.90 (d, 2H); 8.20 (d, 1H).

EXAMPLE 6 (COMPOUND 158) 2-Amino-2-oxoethyl2-[1-(6-fluoro-1-isoquinolyl)-4-piperidyl]ethylcarbamate

6.1. 2-[1-(6-Fluoro-1-isoquinolyl)-4-piperidyl]ethanol

The process is performed as described in Example 4 (step 4.1). Startingwith 1.52 g (8.39 mmol) of 1-chloro-6-fluoroisoquinoline and 1.20 g(9.23 mmol) of 2-(4-piperidyl)ethanol, and after chromatography onsilica gel, eluting with a 95/5/0.5 mixture of dichloromethane, methanoland 28% aqueous ammonia, 0.90 g of pure product is obtained in the formof a yellow paste.

6.2. 2-[1-(6-Fluoro-1-isoquinolyl)-4-piperidyl]ethyl methanesulfonate

The process is performed as described in Example 3 (step 3.2). Startingwith 1.47 g (5.36 mmol) of2-[1-(6-fluoro-1-isoquinolyl)-4-piperidyl]ethanol, obtained in step 6.1,0.675 g (5.89 mmol) of mesyl chloride and 1.13 ml (8.04 mmol) oftriethylamine, 1.80 g of product are obtained in the form of an oil,which is used without further purification in the following step.

6.3.3-{2-[1-(6-Fluoro-1-isoquinolyl)-4-piperidyl]ethyl}-1,3-oxazolidine-2,4-dione

The process is performed according to the method described in Example 3(step 3.3). Starting with 1.8 g (5.10 mmol) of2-[1-(6-fluoro-1-isoquinolyl)-4-piperidyl]ethyl methanesulfonate,obtained in step 6.2, 0.62 g (6.13 mmol) of 1,3-oxazolidine-2,4-dioneand 1.30 ml (10.21 mmol) of 1,1,3,3-tetramethylguanidine, and afterchromatography on silica gel, eluting with a 40/60 mixture of ethylacetate and cyclohexane, 1.34 g of pure product are obtained in the formof an amorphous white solid.

6.4. 2-Amino-2-oxoethyl2-[1-(6-fluoro-1-isoquinolyl)-4-piperidyl]ethylcarbamate

The process is performed according to the procedure described in Example3 (step 3.4). Starting with 0.597 g (1.67 mmol) of3-{2-[1-(6-fluoro-1-isoquinolyl)-4-piperidyl]ethyl}-1,3-oxazolidine-2,4-dione,obtained in Step 6.3, and 14.30 ml (100.20 mmol) of a solution (7M) ofaqueous ammonia in methanol, and after chromatography on silica gel,eluting with a 95/5 mixture of dichloromethane and methanol, followed byrecrystallization from diisopropyl ether, 0.168 g of pure product isobtained in the form of a white solid.

LC-MS:M+H=375 m.p. (° C.): 135–139° C. ¹H NMR (DMSO) δ (ppm): 1.20–1.70(unresolved peak, 5H); 1.80 (broad d, 2H); 2.85 (t, 2H); 3.10 (broad d,2H); 3.70 (broad d, 2H); 4.30 (s, 2H); 6.95–7.20 (unresolved peak, 3H);7.30 (d, 1H); 7.45 (td, 1H); 7.60 (dd, 1H); 8.10 (m, 2H).

EXAMPLE 7 (COMPOUND 172)

2-(Methylamino)-2-oxoethyl2-[1-(4-isoquinolyl)-4-piperidyl]ethylcarbamate hydrochloride

7.1. 2-[1-(4-Isoquinolyl)-4-piperidyl]ethanol

The process is performed according to the protocol described in Example2 (step 2.1). Starting with 1 g (4.81 mmol) of 4-bromoisoquinoline,0.683 g (5.29 mmol) of 2-(4-piperidyl)ethanol, 1.11 g (11.50 mmol) ofsodium tert-butoxide, 0.090 g (0.144 mmol) of BINAP and 0.044 g (0.048mmol) of tris(dibenzylideneacetone)dipalladium, and after chromatographyon silica gel, eluting with a 97/3 and then 95/5 mixture ofdichloromethane and methanol, 0.810 g of product is obtained in the formof a viscous green liquid.

7.2.3-{2-[1-(4-Isoquinolyl)-4-piperidyl]ethyl)-1,3-oxazolidine-2,4-dione

The procedure described in Example 5 (step 5.2) is used. Starting with0.801 g (3.12 mmol) of 2-[1-(4-isoquinolyl)-4-piperidyl]ethanol,prepared in step 7.1, 0.902 g (3.44 mmol) of triphenylphosphine, 0.379 g(3.75 mmol) of 1,3-oxazolidine-2,4-dione and 0.632 g (3.12 mmol) ofdiisopropyl azodicarboxylate (DIAD), and after chromatography on silicagel, eluting with a 98/2 mixture of dichloromethane and methanol, 1 g ofproduct is obtained in the form of a green paste.

7.3. 2-(Methylamino)-2-oxoethyl2-[1-(4-isoquinolyl)-4-piperidyl]ethylcarbamate

The procedure described in Example 1 (step 1.5) is used. Starting with 1g (2.95 mmol) of3-{2-[1-(4-isoquinolyl)-4-piperidyl]ethyl}-1,3-oxazolidine-2,4-dione,obtained in step 7.2, and 7.40 ml (14.73 mmol) of a solution (2M) ofmethylamine in tetrahydrofuran, and after chromatography on silica gel,eluting with a 95/5 mixture of dichloromethane and methanol, 0.410 g ofpure product is obtained in the form of an amorphous white solid. Thisoily residue is then taken up in a solution of hydrochloric acid (5N) inisopropanol and the salt formed is filtered off and then washedsuccessively with acetone and then with diisopropyl ether.

After drying under vacuum at about 90° C., 0.359 g of hydrochloride isobtained in the form of a yellow solid.

LC-MS: M+H=371 m.p. (° C.): 205–210° C. ¹H NMR (DMSO) δ (ppm): 1.30–1.70(unresolved peak, 5H); 1.90 (broad d, 2H); 2.60 (d, 3H); 2.90 (t, 2H);3.15 (m, 2H); 3.50 (broad d, 2H); 4.35 (s, 2H); 7.25 (broad t, 1H); 7.80(broad s, 1H); 8.0 (dd, 1H); 8.05–8.30 (unresolved peak, 3H); 8.45 (d,1H); 9.45 (s, 1H).

EXAMPLE 8 (COMPOUND 126) 2-(Methylamino)-2-oxoethyl2-[1-(2-quinolyl)-4-piperidyl]ethylcarbamate

8.1. 2-[1-(2-Quinolyl)-4-piperidyl]ethanol

The process is performed as in Example 4 (step 4.1). Starting with 2 g(12.20 mmol) of 2-chloroquinoline and 1.58 g (12.20 mmol) of2-(4-piperidyl)-ethanol, and after chromatography on silica gel, elutingwith a 98/2/0.2 and then 95/5/0.5 mixture of dichloromethane, methanoland 28% aqueous ammonia, 2.36 g of pure product are obtained in the formof a pale yellow oil that crystallizes at room temperature.

8.2. 3 {2-[1-(2-Quinolyl)-4-piperidyl]ethyl-1,3-oxazolidine-2,4-dione

The process is performed according to the procedure described in Example5 (step 5.2). Starting with 2.22 g (8.65 mmol) of2-[1-(2-quinolyl)-4-piperidyl]-ethanol, prepared in step 8.1, 2.50 g(9.52 mmol) of triphenylphosphine, 1.05 g (10.38 mmol) of1,3-oxazolidine-2,4-dione and 1.75 g (8.65 mmol) of diisopropylazodicarboxylate (DIAD), and after chromatography on silica gel, elutingwith a 30/70 and then 40/60 mixture of ethyl acetate and cyclohexane,2.63 g of product are obtained in the form of an amorphous white solid.

8.3. 2-(Methylamino)-2-oxoethyl2-[1-(2-quinolyl)-4-piperidyl]ethylcarbamate

The process is performed according to the procedure described in Example1 (step 1.5). Starting with 1.5 g (4.42 mmol) of3{2-[1-(2-quinolyl)-4-piperidyl]ethyl-1,3-oxazolidine-2,4-dione,obtained in step 8.2, and 11 ml (22.10 mmol) of a solution (2M) ofmethylamine in tetrahydrofuran, and after chromatography on silica gel,eluting with a 98/2/0.2 and then 95/5/0.5 mixture of dichloromethane,methanol and 28% aqueous ammonia, followed by crystallization from ethylacetate, 0.405 g of pure product is obtained in the form of a whitesolid.

LC-MS: M+H=371 m.p. (° C.): 125–128° C. ¹H NMR (CDCl₃) δ (ppm):1.20–1.60 (unresolved peak, 5H); 1.85 (broad d, 2H); 2.85 (d, 3H); 3.0(broad t, 2H); 3.30 (broad q, 2H); 4.55 (broad d, 2H); 4.60 (s, 2H);4.85 (broad s, 1H); 6.10 (broad s, 1H); 7.0 (d, 1H); 7.20 (t, 1H); 7.55(m, 2H); 7.70 (d, 1H); 7.90 (d, 1H).

EXAMPLE 9 (COMPOUND 127) 2-Amino-2-oxoethyl2-[1-(2-quinolyl)-4-piperidyl]ethylcarbamate

The process is performed according to the procedure described in Example3 (step 3.4). Starting with 1.14 g (3.36 mmol) of3{2-[1-(2-quinolyl)-4-piperidyl]-ethyl}-1,3-oxazolidine-2,4-dione,described in Example 8 (step 8.2), and 9.60 ml (67.20 mmol) of asolution (7M) of aqueous ammonia in methanol, and after chromatographyon silica gel, eluting with a 95/5 mixture of dichloromethane andmethanol, followed by recrystallization from ethyl acetate, 0.360 g ofpure product is obtained in the form of a white solid.

LC-MS: M+H=357 m.p. (° C.): 135–137° C. ¹H NMR (CDCl₃) δ (ppm):1.15–1.70 (unresolved peak, 5H); 1.85 (broad d, 2H); 2.95 (t, 2H); 3.35(q, 2H); 4.55 (broad d, 2H); 4.60 (s, 2H); 4.85 (broad s, 1H); 5.55(broad s, 1H); 6.05 (broad s, 1H); 7.0 (d, 1H); 7.20 (t, 1H); 7.55 (t,1H); 7.60 (d, 1H); 7.70 (d, 1H); 7.90 (d, 1H).

EXAMPLE 10 (COMPOUND 137) 2-Amino-2-oxoethyl2-[1-(6-chloro-2-quinolyl)-4-piperidyl]ethylcarbamate

10.1. 2-[1-(6-Chloro-2-quinolyl)-4-piperidyl]ethanol

The process is performed as described in Example 4 (step 4.1). Startingwith 2 g (10.10 mmol) of 2,6-dichloroquinoline and 1.44 g (11.10 mmol)of 2-(4-piperidyl)ethanol, and after chromatography on silica gel,eluting with a 98/2 mixture of dichloromethane and methanol, 2.54 g ofpure product are obtained in the form of a white solid.

10.2. 2-[1-(6-Chloro-2-quinolyl)-4-piperidyl]ethyl methanesulfonate

The process is performed as described in Example 3 (step 3.2). Startingwith 2.49 g (8.56 mmol) of2-[1-(6-chloro-2-quinolyl)-4-piperidyl]ethanol, obtained in step 10.1,1.08 g (9.42 mmol) of mesyl chloride and 1.81 ml (12.84 mmol) oftriethylamine, 3.10 g of product are obtained in the form of an oil,which is used without further purification in the following step.

10.3.3-{2-[1-(6-Chloro-2-quinolyl)-4-piperidyl]ethyl}-1,3-oxazolidine-2,4-dione

The process is performed according to the method described in Example 3(step 3.3). Starting with 3 g (8.13 mmol) of2-[1-(6-chloro-2-quinolyl)-4-piperidyl]ethyl methanesulfonate, obtainedin step 10.2, 1.09 g (10.8 mmol) of 1,3-oxazolidine-2,4-dione and 2.30ml (18 mmol) of 1,1,3,3-tetramethylguanidine, and after chromatographyon silica gel, eluting with a 98/2 mixture of dichloromethane andmethanol, 2.57 g of product are obtained.

10.4. 2-Amino-2-oxoethyl2-[1-(6-chloro-2-quinolyl)-4-piperidyl]ethylcarbamate

The process is performed according to the procedure described in Example3 (step 3.4). Starting with 1.28 g (3.42 mmol) of3-{2-[1-(6-chloro-2-quinolyl)-4-piperidyl]ethyl}-1,3-oxazolidine-2,4-dione,obtained in step 10.3, and 22.10 ml (154.08 mmol) of a solution (7M) ofaqueous ammonia in methanol, and after crystallization from ethanol,0.64 g of pure product is obtained in the form of a white solid.

LC-MS: M+H=391 m.p. (° C.): 189–191° C. ¹H NMR (DMSO) δ (ppm): 1.10 (m,2H); 1.40 (m, 2H); 1.60 (m, 1H); 1.80 (broad d, 2H); 2.90 (broad t, 2H);3.05 (m, 2H); 4.30 (s, 2H); 4.50 (broad d, 2H); 7.15 (m, 3H); 7.25 (d,1H); 7.50 (m, 2H); 7.75 (d, 1H); 7.95 (d, 1H).

EXAMPLE 11 (COMPOUND 166) 2-(Methylamino)-2-oxoethyl2-[1-(3-isoquinolyl)-4-piperidyl]ethylcarbamate

11.1. 2-[1-(3-Isoquinolyl)-4-piperidyl]ethanol

The process is performed as described in Example 4 (step 4.1). Startingwith 1 g (6.11 mmol) of 3-chloroisoquinoline and 0.869 g (6.72 mmol) of2-(4-piperidyl)ethanol, and after chromatography on silica gel, elutingwith a 98/2 mixture of dichloromethane and methanol, 0.34 g of pureproduct is obtained in the form of an oil.

11.2. 2-[1-(3-Isoquinolyl)-4-piperidyl]ethyl methanesulfonate

The process is performed as described in Example 3 (step 3.2). Startingwith 0.34 g (1.33 mmol) of 2-[1-(3-isoquinolyl)-4-piperidyl]ethanol,obtained in step 11.1, 0.18 g (1.59 mmol) of mesyl chloride and 0.30 ml(1.99 mmol) of triethylamine, 0.44 g of product is obtained in the formof an oil, which is used without further purification in the followingstep.

11.3.3-{2-[1-(3-Isoquinolyl)-4-piperidyl]ethyl}-1,3-oxazolidine-2,4-dione

The process is performed according to the method described in Example 3(step 3.3). Starting with 0.44 g (1.32 mmol) of2-[1-(3-isoquinolyl)4-piperidyl]-ethyl methanesulfonate, obtained instep 11.2, 0.16 g (1.58 mmol) of 1,3-oxazolidine-2,4-dione and 0.30 g(2.63 mmol) of 1,1,3,3-tetramethylguanidine, and after chromatography onsilica gel, eluting with a 98/2 mixture of dichloromethane and methanol,0.25 g of product is obtained.

11.4. 2-(Methylamino)-2-oxoethyl2-[1-(3-isoquinolyl)-4-piperidyl]ethylcarbamate

The process is performed according to the procedure described in Example1 (step 1.5). Starting with 0.24 g (0.71 mmol) of3-{2-[1-(3-isoquinolyl)-4-piperidyl]ethyl}-1,3-oxazolidine-2,4-dione,obtained in step 11.3, and 1.8 ml (3.53 mmol) of a solution (2M) ofmethylamine in tetrahydrofuran, and after chromatography on silica gel,eluting with a 98/2 and then 96/4 mixture of dichloromethane andmethanol, followed by crystallization from diisopropyl ether, 0.16 g ofpure product is obtained in the form of a white solid.

LC-MS: M+H=371 m.p. (° C.): 156–158° C. ¹H NMR (CDCl₃) δ (ppm):1.20–1.70 (unresolved peak, 5H); 1.85 (d, 2H); 2.90 (m, 5H); 3.30 (q,2H); 4.40 (d, 2H); 4.60 (s, 2H); 4.85 (broad s, 1H); 6.10 (broad s, 1H);6.80 (s, 1H); 7.30 (m, 1H); 7.60 (m, 2H); 7.80 (d, 1H); 8.95 (s, 1H).

EXAMPLE 12 (COMPOUND 128) 2-(Methylamino)-2-oxoethyl2-[4-fluoro-1-(2-quinolyl)-4-piperidyl]ethylcarbamate

12.1. tert-Butyl 4-hydroxy-4-(2-hydroxyethyl)-1-piperidinecarboxylate

A solution of 31.20 g (108.50 mmol) of tert-butyl4-(2-ethoxy-2-oxoethyl)-4-hydroxy-1-piperidinecarboxylate (WO 02/16352)in 150 ml of tetrahydrofuran is added dropwise to a suspension of 4.12 g(108.50 mmol) of lithium aluminium hydride in 150 ml of tetrahydrofuran.The mixture is stirred at room temperature for 2 hours and is thenworked up as described in Example 2 (step 2.4).

26 g of product are obtained in the form of a yellow oil, which is usedwithout further purification in the following step.

12.2. tert-Butyl4-(2-{[tert-butyldiphenylsilyl]oxy}ethyl)-4-hydroxy-1-piperidine-carboxylate

A solution of 21.50 ml (82.50 mmol) of tert-butyldiphenylsilyl chloridein 15 ml of dichloromethane is added dropwise, under an inertatmosphere, to a solution of 18.4 g (75 mmol) of tert-butyl4-hydroxy-4-(2-hydroxyethyl)-1-piperidinecarboxylate, obtained in step12.1, and 11.60 ml (82.50 mmol) of triethylamine in 100 ml ofdichloromethane, cooled to about 0° C. The mixture is allowed to warm toroom temperature and stirring is then continued for 12 hours. Saturatedaqueous ammonium chloride solution is added to the reaction medium. Theaqueous phase is separated out and extracted twice with dichloromethane,the combined organic phases are washed with saturated aqueous sodiumchloride solution and dried over sodium sulfate, and the filtrate isconcentrated under reduced pressure. The residue thus obtained ispurified by chromatography on silica gel, eluting with a 10/90 and then20/80 mixture of ethyl acetate and cyclohexane.

33.48 g of product are thus obtained in the form of a yellow oil.

12.3. tert-Butyl4-(2-{[tert-butyl(diphenyl)silyl]oxy}ethyl)-4-fluoro-1-piperidinecarboxylate

A solution of 1.70 ml (13.40 mmol) of1,1′-[(trifluoro-λ⁴-sulfanyl)imino]diethane (DAST) in 10 ml ofdichloromethane is added dropwise, under an inert atmosphere, to asolution of 5 g (10.34 mmol) of tert-butyl4-(2-{[tert-butyl(diphenyl)silyl]oxy}ethyl)-4-hydroxy-1-piperidinecarboxylate,obtained in step 12.2, in 100 ml of dichloromethane, cooled to about 0°C. The mixture is allowed to warm to room temperature and stirring isthen continued for 12 hours. Saturated aqueous sodium hydrogen carbonatesolution is added to the reaction medium. The aqueous phase is separatedout and extracted three times with dichloromethane, and the combinedorganic phases are washed with saturated aqueous sodium chloridesolution and dried over sodium sulfate. The filtrate is concentratedunder reduced pressure and the residue thus obtained is then purified bychromatography on silica gel, eluting with a 10/90 mixture of ethylacetate and cyclohexane. 4.65 g of product are thus obtained in the formof an orange-coloured oil. 0.60 ml of a solution of osmium tetroxide(2.5%) in tert-butanol is added at room temperature to a solution of4.50 g of this oily residue and 1.25 g (10.7 mmol) of N-methylmorpholineoxide (NMO) in a mixture of 8 ml of acetone and 6 ml of water. Stirringis continued for 21 hours. The residue is taken up in ethyl acetate andwater, the aqueous phase is separated out and extracted twice with ethylacetate, and the combined organic phases are washed with saturatedaqueous sodium chloride solution and dried over sodium sulfate. Afterevaporating off the solvent, the residue obtained is purified bychromatography on silica gel, eluting with a 6/94 mixture of ethylacetate and cyclohexane.

3.40 g of product are thus obtained in the form of a pale yellow oil.

12.4. 4-(2-{[tert-butyl(diphenyl)silyl]oxy}ethyl)-4-fluoropiperidine

2.80 ml (37.06 mmol) of trifluoroacetic acid are added slowly to asolution of 3 g (6.17 mmol) of tert-butyl4-(2-{[tert-butyldiphenylsilyl]oxy}ethyl)-4-fluoro-1-piperidinecarboxylate,obtained in step 12.3, in 20 ml of dichloromethane. Stirring iscontinued at room temperature for 5 hours. The reaction mixture ispoured into a mixture of ice-water and 28% aqueous ammonia. The phasesare separated by settling, the aqueous phase is extracted twice withdichloromethane and the combined organic phases are washed withsaturated aqueous sodium chloride solution, dried over sodium sulfateand concentrated under reduced pressure.

2.30 g of product are obtained in the form of a yellow oil, which isused without further purification in the following step.

12.5.2-[4-(2-{[tert-butyldiphenylsilyl]oxy}ethyl)-4-fluoro-1-piperidyl]quinoline

The process is performed as described in Example 2 (step 2.1). Startingwith 1.18 g (5.68 mmol) of 2-bromoquinoline (Eur. J. Org. Chem. 2002,4181–4184), 2.30 g (5.98 mmol) of4-(2-{[tert-butyl(diphenyl)silyl]oxy}ethyl)-4-fluoropiperidine, obtainedin step 12.4, 0.66 g (6.81 mmol) of sodium tert-butoxide, 0.149 g (0.239mmol) of BINAP and 0.074 g (0.081 mmol) oftris(dibenzylideneacetone)dipalladium, and after chromatography onsilica gel, eluting with a 10/90 mixture of ethyl acetate andcyclohexane, 2.15 g of pure product are obtained in the form of anorange-coloured oil.

12.6. 2-[4-Fluoro-1-(2-quinolyl)-4-piperidyl]ethanol

0.40 g (1.26 mmol) of n-tetrabutylammonium fluoride trihydrate is addedto a solution of 2.15 g (4.19 mmol) of2-[4-(2-{[tert-butyldiphenylsilyl]oxy}ethyl)-4-fluoro-1-piperidyl]quinoline,obtained in step 12.5, in 20 ml of tetrahydrofuran. Stirring iscontinued at room temperature for 4 hours. The mixture is concentratedto dryness and the residue obtained is then purified by chromatographyon silica gel, eluting with a 35/65 and then 40/60 mixture of ethylacetate and cyclohexane.

0.61 g of product is obtained in the form of an orange-coloured oil.

12.7. 2-[4-Fluoro-1-(2-quinolyl)-4-piperidyl]ethyl methanesulfonate

The process is performed as described in Example 3 (step 3.2). Startingwith 0.61 g (2.22 mmol) of2-[4-fluoro-1-(2-quinolyl)-4-piperidyl]ethanol, obtained in step 12.6,0.280 g (2.45 mmol) of mesyl chloride and 0.35 ml (2.45 mmol) oftriethylamine, 0.80 g of product is obtained in the form of anorange-coloured oil, which is used without further purification in thefollowing step.

12.8.3-{2-[4-Fluoro-1-(2-quinolyl)-4-piperidyl]ethyl}-1,3-oxazolidine-2,4-dione

The process is performed according to the method described in Example 3(step 3.3). Starting with 0.780 g (2.22 mmol) of2-[4-fluoro-1-(2-quinolyl)-4-piperidyl]ethyl methanesulfonate, obtainedin step 12.7, 0.27 g (2.66 mmol) of 1,3-oxazolidine-2,4-dione and 0.51 g(4.43 mmol) of 1,1,3,3-tetramethylguanidine, and after chromatography onsilica gel, eluting with a 99/1 mixture of dichloromethane and methanol,0.520 g of pure product is obtained in the form of a beige-colouredsolid.

12.9. 2-(Methylamino)-2-oxoethyl2-[4-fluoro-1-(2-quinolyl)-4-piperidyl]ethylcarbamate

The process is performed according to the procedure described in Example1 (step 1.5). Starting with 0.52 g (1.46 mmol) of3-{2-[4-fluoro-1-(2-quinolyl)-4-piperidyl]ethyl}-1,3-oxazolidine-2,4-dione,obtained in step 12.8, and 3.6 ml (7.28 mmol) of a solution (2M) ofmethylamine in tetrahydrofuran, and after chromatography on silica gel,eluting with a 99/1 mixture of ethyl acetate and methanol, followed bycrystallization from diethyl ether, 0.390 g of pure product is obtainedin the form of a white solid.

LC-MS: M+H=389 m.p. (° C.): 147–149° C. ¹H NMR (CDCl₃) δ (ppm):1.70–2.10 (unresolved peak, 6H); 2.90 (d, 3H); 3.40 (broad t, 2H); 3.50(q, 2H); 4.40 (broad d, 2H); 4.60 (s, 2H); 5.15 (broad s, 1H); 6.15(broad s, 1H); 7.05 (d, 1H); 7.25 (t, 1H); 7.55 (t, 1H); 7.65 (d, 1H);7.75 (d, 1H); 7.95 (d, 1H).

EXAMPLE 13 (COMPOUND 49) 2-(Methylamino)-2-oxoethyl2-[1-(6-isobutyl-2-pyridyl)-4-piperidyl]ethylcarbamate

13.1. 2-[1-(6-Bromo-2-pyridyl)-4-piperidyl]ethanol

The process is performed as described in Example 4 (step 4.1). Startingwith 30.20 g (127 mmol) of 2,6-dibromopyridine and 16.45 g (127 mmol) of2-(4-piperidyl)ethanol, and after chromatography on silica gel, elutingwith a 30/70 mixture of ethyl acetate and cyclohexane, 7 g of pureproduct are obtained in the form of an oil.

13.2. 2-[1-(6-Bromo-2-pyridyl)-4-piperidyl]ethyl methanesulfonate

The process is performed as described in Example 3 (step 3.2). Startingwith 7 g (24.50 mmol) of 2-[1-(6-bromo-2-pyridyl)-4-piperidyl]ethanol,obtained in step 13.1, 2.50 ml (26.90 mmol) of mesyl chloride and 3.80ml (26.90 mmol) of triethylamine, 8.68 g of product are obtained in theform of an oil, which is used without further purification in thefollowing step.

13.3.3-{2-[1-(6-Bromo-2-pyridyl)-4-piperidyl]ethyl}-1,3-oxazolidine-2,4-dione

The process is performed according to the method described in Example 3(step 3.3). Starting with 8.68 g (23.80 mmol) of2-[1-(6-bromo-2-pyridyl)-4-piperidyl]ethyl methanesulfonate, obtained instep 13.2, 2.90 g (28.60 mmol) of 1,3-oxazolidine-2,4-dione and 6 ml(47.60 mmol) of 1,1,3,3-tetramethylguanidine, and after chromatographyon silica gel, eluting with a 97/3 mixture of dichloromethane andmethanol, 4.52 g of product are obtained in the form of an oil.

13.4.3-{2-[1-(6-Isobutyl-2-pyridyl)-4-piperidyl]ethyl}-1,3-oxazolidine-2,4-dione

2 g (5.43 mmol) of3-{2-[1-(6-bromo-2-pyridyl)-4-piperidyl]ethyl}-1,3-oxazolidine-2,4-dione,prepared in step 13.3, and 0.20 g (0.271 mmol) ofdichlorobis(triphenylphosphine)palladium (Pd(PPh₃)₂Cl₂) suspended in 10ml of tetrahydrofuran are introduced under an inert atmosphere. 22 ml(10.80 mmol) of a solution (0.5 M) of bromo(isobutyl)zinc intetrahydrofuran are then added. Stirring is continued at roomtemperature for 17 hours. The reaction mixture is poured into water andethyl acetate. The phases are separated by settling, the aqueous phaseis extracted twice with ethyl acetate, the combined organic phases aredried over sodium sulfate and the filtrate is concentrated under reducedpressure. The residue thus obtained is purified by chromatography onsilica gel, eluting with a 20/80 mixture of ethyl acetate andcyclohexane.

1.41 g of product are obtained in the form of a white solid.

m.p. (° C.): 94–96° C.

13.5. 2-(Methylamino)-2-oxoethyl2-[1-(6-isobutyl-2-pyridyl)-4-piperidyl]ethyl-carbamate

The process is performed according to the procedure described in Example1 (step 1.5). Starting with 0.72 g (2.08 mmol) of3-{2-[1-(6-isobutyl-2-pyridyl)-4-piperidyl]ethyl}-1,3-oxazolidine-2,4-dione,obtained in step 13.4, and 5.20 ml (10.40 mmol) of a solution (2M) ofmethylamine in tetrahydrofuran, and after chromatography on silica gel,eluting with a 95/5/0.5 mixture of dichloromethane, methanol and 28%aqueous ammonia, followed by crystallization from diisopropyl ether,0.540 g of pure product is obtained in the form of a white solid.

LC-MS: M+H=377 m.p. (° C.): 97–99° C. ¹H NMR (DMSO) δ (ppm): 0.85 (d,6H); 1.05 (m, 2H); 1.20–1.60 (unresolved peak, 3H); 1.70 (broad d, 2H);2.0 (m, 1H); 2.40 (d, 2H); 2.55 (d, 3H); 2.70 (broad t, 2H); 3.05 (broadq, 2H); 4.20 (broad d, 2H); 4.30 (s, 2H); 6.35 (d, 1H); 6.55 (d, 1H);7.15 (broad t, 1H); 7.40 (dd, 1H); 7.75 (broad s, 1H).

EXAMPLE 14 (COMPOUND 58) 2-Amino-2-oxoethyl2-[1-(6-phenyl-2-pyridyl)-4-piperidyl]methylcarbamate

14.1.3-{2-[1-(6-Phenyl-2-pyridyl)-4-piperidyl]methyl}-1,3-oxazolidine-2,4-dione

0.20 g (0.56 mmol) of3-{2-[1-(6-bromo-2-pyridyl)-4-piperidyl]methyl}-1,3-oxazolidine-2,4-dione,prepared according to the procedure described in Example 13 (steps 13.1,13.2 and 13.3), 0.089 g (0.73 mmol) of phenylboronic acid and 0.480 g(2.25 mmol) of hydrated potassium phosphate suspended in 3 ml of1,2-dimethoxyethane are introduced under an inert atmosphere. 0.040 g(0.0346 mmol) of tetrakis(triphenylphosphine)palladium is then added.The reaction mixture is then maintained at about 85° C. for 16 hours.The resulting mixture is concentrated under reduced pressure. Theresidue is taken up in ethyl acetate and water, the aqueous phase isseparated out and extracted twice with ethyl acetate, the combinedorganic phases are dried over sodium sulfate and the filtrate isconcentrated under reduced pressure. The residue thus obtained ispurified by chromatography on silica gel, eluting with a 40/60 mixtureof ethyl acetate and cyclohexane.

0.175 g of product is obtained.

14.2. 2-Amino-2-oxoethyl2-[1-(6-phenyl-2-pyridyl)-4-piperidyl]methylcarbamate

The process is performed according to the procedure described in Example3 (step 3.4). Starting with 0.175 g (0.499 mmol) of3-{2-[1-(6-phenyl-2-pyridyl)-4-piperidyl]methyl}-1,3-oxazolidine-2,4-dione,obtained in step 14.1, and 2.5 ml (17.45 mmol) of a solution (7M) ofaqueous ammonia in methanol, 0.070 g of pure product is obtained in theform of a white solid, after crystallization from ethyl acetate.

LC-MS: M+H=369 m.p. (° C.): 131–132° C. ¹H NMR (CDCl₃) δ (ppm):1.20–1.90 (unresolved peak, 5H); 2.90 (broad t, 2H); 3.20 (t, 2H); 4.50(broad d, 2H); 4.60 (s, 2H); 5.0 (broad s, 1H); 5.55 (broad s, 1H); 6.15(broad s, 1H); 6.65 (d, 1H); 7.10 (d, 1H); 7.35–7.60 (m, 4H); 8.15 (dd,2H).

EXAMPLE 15 (COMPOUND 130) 2-(Methylamino)-2-oxoethyl2-[1-(5-chloro-2-quinolyl)-4-piperidyl]ethylcarbamate

15.1. 2-[1-(5-Chloro-2-quinolyl)-4-piperidyl]ethanol

The process is performed as described in Example 4 (step 4.1). Startingwith 4.78 g (24.14 mmol) of 2-chloro-5-chloroquinoline (J. Med. Chem.,2002, 45, 3130–3137) and 3.43 g (26.55 mmol) of 2-(4-piperidyl)ethanol,7 g of product are obtained in the form of an oil, which is used withoutfurther purification in the following step.

15.2. 2-[1-(5-Chloro-2-quinolyl)-4-piperidyl]ethyl methanesulfonate

The process is performed as described in Example 3 (step 3.2). Startingwith 7 g (24.07 mmol) of 2-[1-(5-chloro-2-quinolyl)-4-piperidyl]ethanol,obtained in step 15.1, 3.31 g (28.89 mmol) of mesyl chloride and 5.10 ml(36.11 mmol) of triethylamine, 8.70 g of product are obtained in theform of an oil, which is used without further purification in thefollowing step.

15.3.3-{2-[1-(5-Chloro-2-quinolyl)-4-piperidyl]ethyl}-1,3-oxazolidine-2,4-dione

The process is performed according to the method described in Example 3(step 3.3). Starting with 8.7 g (23.58 mmol) of2-[1-(5-chloro-2-quinolyl)-4-piperidyl]ethyl methanesulfonate, obtainedin step 15.2, 2.86 g (28.30 mmol) of 1,3-oxazolidine-2,4-dione and 5.43g (47.17 mmol) of 1,1,3,3-tetramethyl-guanidine, and afterchromatography on silica gel, eluting with a 99.5/0.5 mixture ofdichloromethane and methanol, 6.40 g of product are obtained in the formof a white solid.

m.p. (° C.): 136° C.

15.4. 2-(Methylamino)-2-oxoethyl2-[1-(5-chloro-2-quinolyl)-4-piperidyl]ethylcarbamate

The process is performed according to the procedure described in Example1 (step 1.5). Starting with 6.40 g (17.12 mmol) of3-{2-[1-(5-chloro-2-quinolyl)-4-piperidyl]ethyl}-1,3-oxazolidine-2,4-dione,obtained in step 15.3, and 60 ml (119.84 mmol) of a solution (2M) ofmethylamine in tetrahydrofuran, and after chromatography on silica gel,eluting with a 98/2 and then 96/4 mixture of dichloromethane andmethanol, followed by crystallization from diisopropyl ether, 5.14 g ofproduct are obtained in the form of a white solid.

LC-MS: M+H=405 m.p. (° C.): 158–162° C. ¹H NMR (CDCl₃) δ (ppm):1.10–1.80 (unresolved peak, 5H); 1.9 (broad d, 2H); 2.90 (d, 3H); 3.0(m, 2H); 3.30 (q, 2H); 4.60 (m, 4H); 4.85 (broad s, 1H); 6.10 (broad s,1H); 7.05 (d, 1H); 7.25 (d, 1H); 7.40 (dd, 1H); 7.60 (d, 1H); 8.30 (s,1H).

Table 1 below illustrates the chemical structures and physicalproperties of a number of compounds according to the invention.

In this table:

-   in the “base or salt” column, “base” represents a compound in free    base form, whereas “HCl” represents a compound in hydrochloride    form;-   OMe represents a methoxy group.

TABLE 1 (I)

base or No R₁ m n A B R₃ salt m.p. (° C.) 1.

2 2 N (CH₂)₃ CH₂CONHCH₃ base 131 2.3.

22 22 NN (CH₂)₂(CH₂)₂ CH₂CONH₂CH₂CONHCH₃ basebase 417*165–166 4.5.

22 22 NN (CH₂)₂(CH₂)₂ CH₂CONH₂CH₂CONHCH₃ basebase 144–145138–139 6.7.

22 22 NN (CH₂)₂(CH₂)₂ CH₂CONH₂CH₂CONHCH₃ basebase 173–174196–197 8.9.

22 22 NN (CH₂)₂(CH₂)₂ CH₂CONH₂CH₂CONHCH₃ basebase 157–158225–226 10.11.

22 22 NN (CH₂)₂(CH₂)₂ CH₂CONH₂CH₂CONHCH₃ basebase 121–122141–142 12.13.

22 22 NN (CH₂)₂(CH₂)₂ CH₂CONH₂CH₂CONHCH₃ basebase 139–140170–171 14.15.

22 22 NN (CH₂)₂(CH₂)₂ CH₂CONH₂CH₂CONHCH₃ basebase 128–129153–154 16.17.

22 22 NN (CH₂)₂(CH₂)₂ CH₂CONH₂CH₂CONHCH₃ basebase 160–161148–149 18.19.

22 22 NN (CH₂)₂(CH₂)₂ CH₂CONH₂CH₂CONHCH₃ basebase 156–157157–158 20.21.

22 22 NN (CH₂)₂(CH₂)₂ CH₂CONH₂CH₂CONHCH₃ basebase 178–179432* 22.23.

22 22 NN (CH₂)₂(CH₂)₂ CH₂CONH₂CH₂CONHCH₃ basebase 158–159180–181 24.25.

22 22 NN (CH₂)₂(CH₂)₂ CH₂CONH₂CH₂CONHCH₃ basebase 185–186193–194 26.27.

22 22 NN (CH₂)₂(CH₂)₂ CH₂CONH₂CH₂CONHCH₃ basebase 153–154125–126 28.29.

22 22 NN (CH₂)₂(CH₂)₂ CH₂CONH₂CH₂CONHCH₃ basebase 193–194176–177 30.31.

22 22 NN (CH₂)₂(CH₂)₂ CH₂CONH₂CH₂CONHCH₃ basebase 160–161156–157 32.33.

22 22 NN (CH₂)₂(CH₂)₂ CH₂CONH₂CH₂CONHCH₃ basebase 189–190196–197 34.

2 3 N (CH₂)₃ CH₂CONHCH₃ base 100(dec.) 35.

2 3 N (CH₂)₃ CH₂CONHCH₃ HCl 451* 36.

2 3 N (CH₂)₃ CH₂CONHCH₃ HCl 172–174 37.

2 3 N (CH₂)₃ CH₂CONHCH₃ base 118–122 38.39.

22 22 NN (CH₂)₂(CH₂)₃ CH₂CONHCH₃CH₂CONHCH₃ HClHCl 16616740.41.42. 43.44.45.

111 222 111 222 CHCHCH CHCHCF CH₂CH₂CH₂ (CH₂)₂(CH₂)₂(CH₂)₂CH₂CONH₂CH₂CONHCH₃CH₂CONHCH₃(cyclopropyl)CH₂CONHCH₃CH₂CONH₂CH₂CONHCH₃basebasebase basebasebase 149–151137–139119–121 110–112140–142127–12846.

2 2 CH (CH₂)₂ CH₂CONHCH₃ HCl 168–170 47.

2 2 CH (CH₂)₂ CH₂CONHCH₃ HCl  95–100 48.

2 2 CH (CH₂)₂ CH₂CONHCH₃ base 113–115 49.50.

22 22 CHCH (CH₂)₂(CH₂)₂ CH₂CONHCH₃CH₂CONH₂ basebase 97–99107–109 51.

2 2 CH (CH₂)₂ CH₂CONHCH₃ base 108–110 52.

2 2 CH (CH₂)₂ CH₂CONHCH₃ base  98–100 53.

2 2 CH (CH₂)₂ CH₂CONHCH₃ base 123–125 54.55.56.

222 222 CHCHCH —CH₂(CH₂)₂ CH₂CONH₂CH₂CONH₂CH₂CONH₂ basebasebase169148–149131–132 57.58.59.

222 222 CHCHCH —CH₂(CH₂)₂ CH₂CONH₂CH₂CONH₂CH₂CONH₂ basebasebase153131–132116–117 60.61.62.

222 222 CHCHCH —CH₂(CH₂)₂ CH₂CONH₂CH₂CONH₂CH₂CONH₂ basebasebase190–191155–156155–156 63.64.65.

222 222 CHCHCH —CH₂(CH₂)₂ CH₂CONH₂CH₂CONH₂CH₂CONH₂ basebasebase159–160132134–135 66.67.

22 22 CHCH CH₂(CH₂)₂ CH₂CONH₂CH₂CONH₂ basebase 146–147332* 68.69.70.

222 222 CHCHCH —CH₂(CH₂)₂ CH₂CONH₂CH₂CONH₂CH₂CONH₂ basebasebase131–132129–13086–87 71.72.73.

222 222 CHCHCH —CH₂(CH₂)₂ CH₂CONH₂CH₂CONH₂CH₂CONH₂ basebasebase58–59387*58–59 74.75.

22 22 CHCH CH₂(CH₂)₂ CH₂CONH₂CH₂CONH₂ basebase 152–153163 76.77.

22 22 CHCH (CH₂)₂(CH₂)₂ CH₂CONHCH₃CH₂CONH₂ basebase 121–123137–13978.79.

22 22 CHCH CH₂(CH₂)₂ CH₂CONH₂CH₂CONH₂ basebase 327*162–163 80.81.82.

222 222 CHCHCH —CH₂(CH₂)₂ CH₂CONH₂CH₂CONH₂CH₂CONH₂ basebasebase16876174–175 83.84.

22 22 CHCH CH₂(CH₂)₂ CH₂CONH₂CH₂CONH₂ basebase 169–170145–146 85.86.

22 22 CHCH (CH₂)₂(CH₂)₂ CH₂CONH₂CH₂CONHCH₃ basebase 119–121109–11187.88.

22 22 CHCH CH₂(CH₂)₂ CH₂CONH₂CH₂CONH₂ basebase 169–170164–165 89.

2 2 CH CH₂ CH₂CONH₂ base 174–175 90.91.

22 22 CHCH CH₂(CH₂)₂ CH₂CONH₂CH₂CONH₂ basebase 162–163151–152 92.93.

22 22 CHCH —CH₂ CH₂CONH₂CH₂CONH₂ basebase 195–196229–230 94.95.96.

222 222 CHCHCH —CH₂(CH₂)₂ CH₂CONH₂CH₂CONH₂CH₂CONH₂ basebasebase194–195222–223182 97.98.

22 22 CHCH (CH₂)₂(CH₂)₂ CH₂CONH₂CH₂CONHCH₃ basebase 196–199161–16399.100.

22 22 CHCH CH₂(CH₂)₂ CH₂CONH₂CH₂CONH₂ basebase 157–158175–176 101.

2 2 CH CH₂ CH₂CONH₂ base 163–164 102.

2 2 CH (CH₂)₂ CH₂CONH₂ base 418* 103.

2 2 CH CH₂ CH₂CONH₂ base 190–191 104.

2 2 CH (CH₂)₂ CH₂CONH₂ base 165–166 105.106.

22 22 CHCH CH₂(CH₂)₂ CH₂CONH₂CH₂CONH₂ basebase 323*202–203 107.

2 2 CH CH₂ CH₂CONH₂ base 172–173 108.

2 2 CH CH₂ CH₂CONH₂ base 370* 109.

2 2 CH CH₂ CH₂CONH₂ base 177–178 110.111.

22 22 CHCH CH₂(CH₂)₂ CH₂CONH₂CH₂CONH₂ basebase 202–203185–186 112.113.

22 22 CHCH CH₂(CH₂)₂ CH₂CONH₂CH₂CONH₂ basebase 165–166126–127 114.115.

22 22 CHCH CH₂(CH₂)₂ CH₂CONH₂CH₂CONH₂ basebase 309*159–160 116.117.

22 22 CHCH CH₂(CH₂)₂ CH₂CONH₂CH₂CONH₂ basebase 161–162126–127 118.119.

22 22 CHCH CH₂(CH₂)₂ CH₂CONH₂CH₂CONH₂ basebase 158–159174–175 120.

2 2 CH (CH₂)₂ CH₂CONH₂ base 204–205 121.122.

22 22 CHCH CH₂(CH₂)₂ CH₂CONH₂CH₂CONH₂ basebase 229–230228–229123.124.125.126.127.128.129.

2222222 2222222 CHCHCHCHCHCFC(OH) CH₂CH₂CH₂(CH₂)₂(CH₂)₂(CH₂)₂(CH₂)₂CH₂CONHCH₃CH₂CONH₂CH(CH₃)CONHCH₃CH₂CONHCH₃CH₂CONH₂CH₂CONHCH₃CH₂CONHCH₃basebasebasebasebasebasebase153–157206–212129–130126–128135–137147–14982–90 130.131.

22 22 CHCH (CH₂)₂(CH₂)₂ CH₂CONHCH₃CH₂CONH₂ basebase 158–162171–175 132.

2 2 CH (CH₂)₂ CH₂CONHCH₃ base 162–163 133.

2 2 CH (CH₂)₂ CH₂CONHCH₃ base 154–156 134.135.136.137.

2222 2222 CHCHCHCH CH₂CH₂(CH₂)₂(CH₂)₂CH₂CONHCH₃CH₂CONH₂CH₂CONHCH₃CH₂CONH₂ basebasebasebase147–151207–208155–157189–191 138.139.140.141.

2222 2222 CHCHCHCH (CH₂)₂(CH₂)₂(CH₂)₂(CH₂)₂CH₂CONH₂CH₂CONHCH₃CH₂CONHCH₂CH₃CH₂CONHCH₂(cyclopropyl) basebasebasebase163–165135–137114–116 95–100 142.143.

22 22 CHCH (CH₂)₂(CH₂)₂ CH₂CONH₂CH₂CONHCH₃ basebase 191–193149–151144.145.

22 22 CHCH (CH₂)₂(CH₂)₂ CH₂CONHCH₃CH₂CONH₂ basebase 146–150171–173146.147.

22 22 CHCH (CH₂)₂(CH₂)₂ CH₂CONHCH₃CH₂CONH₂ basebase 140–142160–162148.149.

22 22 CHCH (CH₂)₂(CH₂)₂ CH₂CONHCH₃CH₂CONH₂ HClHCl 148–150219–221 150.

2 2 CH (CH₂)₂ CH₂CONHCH₃ base 130–132 151.152.153.154.155.156.157.

1122222 2222222 CHCHCHCHCHCHCH CH₂CH₂—CH₂(CH₂)₂(CH₂)₂(CH₂)₃CH₂CONH₂CH₂CONHCH₃CH₂CONHCH₃CH₂CONHCH₃CH₂CONHCH₃CH₂CONH₂CH₂CONHCH₃basebaseHClHClHClHClHCl 109–111 99–102232–237208–212132–136120–124385*158.159.

22 22 CHCH (CH₂)₂(CH₂)₂ CH₂CONH₂CH₂CONHCH₃ basebase 135–139144–148 160.

2 2 CH (CH₂)₂ CH₂CONHCH₃ base 134–136 161.162.163.

222 222 CHCHCH CH₂(CH₂)₂(CH₂)₂ CH₂CONHCH₃CH₂CONHCH₃CH₂CONH₂ HClbasebase387*100–104118–120 164.

2 2 CH (CH₂)₂ CH₂CONHCH₃ HCl 186–188 165.

2 2 CH (CH₂)₂ CH₂CONHCH₃ base 80–86 166.167.

22 22 CHCH (CH₂)₂(CH₂)₂ CH₂CONHCH₃CH₂CONH₂ basebase 156–158176–178 168.

2 2 CH (CH₂)₂ CH₂CONHCH₃ base 148–150 169.

2 2 CH (CH₂)₂ CH₂CONHCH₃ base 154–156 170.171.

22 22 CHCH (CH₂)₂(CH₂)₂ CH₂CONH₂CH₂CONHCH₃ basebase 156–158156–158 172.

2 2 CH (CH₂)₂ CH₂CONHCH₃ HCl 205–210 173.174.

22 22 CHCH (CH₂)₂(CH₂)₂ CH₂CONH₂CH₂CONHCH₃ basebase 419*105–106 175.176.

22 22 CHCH (CH₂)₂(CH₂)₂ CH₂CONH₂CH₂CONH₂ basebase 129–130112–113 177.

2 2 CH CH₂ CH₂CONH₂ base 180–181 178.179.180.

222 222 CHCHCH CH₂(CH₂)₂(CH₂)₂ CH₂CONH₂CH₂CONHCH₃CH₂CONH₂ basebasebase244–245146–150169–171 181.182.

22 22 CHCH CH₂(CH₂)₂ CH₂CONH₂CH₂CONH₂ basebase 137–138208–209 183.184.

22 22 CHCH CH₂(CH₂)₂ CH₂CONH₂CH₂CONH₂ basebase 183–184172–173 185.186.

22 22 CHCH CH₂(CH₂)₂ CH₂CONH₂CH₂CONH₂ basebase 187–188191–192 187.

2 2 CH CH₂ CH₂CONH₂ base 222–223 188.189.

22 22 CHCH CH₂(CH₂)₂ CH₂CONH₂CH₂CONH₂ basebase 149–150167–168 190.191.

22 22 CHCH CH₂(CH₂)₂ CH₂CONH₂CH₂CONH₂ basebase 220–221201–202 *M + H(LC-MS) dec. = decomposition of the product

The compounds of the invention underwent pharmacological trials todetermine their inhibitory effect on the enzyme FAAH (Fatty Acid AmideHydrolase).

The inhibitory activity was demonstrated in a radioenzymatic test basedon measuring the product of hydrolysis (ethanolamine [1-³H]) ofanandamide[ethanolamine 1-³H] with FAAH (Life Sciences (1995), 56,1999–2005 and Journal of Pharmacology and Experimented Therapeutics(1997), 283, 729–734). Thus, mouse brains (minus the cerebellum) areremoved and stored at −80° C. Membrane homogenates are preparedextemporaneously by homogenizing the tissues using a Polytron blender in10 mM tris-HCl buffer (pH 8.0) containing 150 mM NaCl and 1 mM EDTA. Theenzymatic reaction is then performed in 70 μl of buffer containingfatty-acid-free bovine serum albumin (1 mg/ml). To test compounds atdifferent concentrations, anandamide[ethanolamine 1-³H] (specificactivity of 15–20 Ci/mmol) diluted to 10 μM with cold anandamide, andthe membrane preparation (400 μg of frozen tissue per test) aresuccessively added. After 15 minutes at 25° C., the enzymatic reactionis quenched by adding 140 μL of chloroform/methanol (2:1). The mixtureis stirred for 10 minutes and then centrifuged for 15 minutes at 3500 g.An aliquot (30 μL) of the aqueous phase containing the ethanolamine[1-³H] is counted by liquid scintillation. Under these conditions, themost active compounds of the invention have IC₅₀ values (concentrationthat inhibits 50% of the control enzymatic activity of FAAH) of between0.001 and 1 μM.

Table 2 below shows the IC₅₀ values of a few compounds according to theinvention.

TABLE 2 Compound No. IC₅₀ 47 85 μM 126 113 μM  166 87 μM

It is thus seen that the compounds according to the invention haveinhibitory activity on the enzyme FAAH.

The in vivo activity of the compounds of the invention was evaluated ina test of analgesia.

Thus, the intraperitoneal (i.p.) administration of PBQ(phenylbenzoquinone, 2 mg/kg in 0.9% sodium chloride solution containing5% ethanol) to male OFI mice weighing 25 to 30 g, causes abdominaltractions, on average 30 torsions or contractions during the period of 5to 15 minutes after injection. The test compounds are administeredorally or intraperitoneally as a 0.5% suspension in Tween 80, 60 minutesor 120 minutes before the administration of PBQ. Under these conditions,the most powerful compounds of the invention produce a 35% to 70%reduction in the number of tractions induced with PBQ, within a doserange of between 1 and 30 mg/kg.

Table 3 below shows the results of the analgesia test for a fewcompounds according to the invention.

TABLE 3 Reduction in the number Compound No. of tractions (%) 47 −63%(b) 126 −43% (b) 166 −62% (a) (a) 1 mg/kg p.o. at 2 hours; (b) 3 mg/kgp.o. at 1 hour

The enzyme FAAH (Chemistry and Physics of Lipids, (2000), 108, 107–121)catalyses the hydrolysis of the endogenous amide and ester derivativesof various fatty acids such as N-arachidonoylethanolamine (anandamide),N-palmitoylethanolamine, N-oleoylethanolamine, oleamide or2-arachidonoylglycerol. These derivatives exert differentpharmacological activities by interacting, inter alia, with thecannabinoid and vanilloid receptors.

The compounds of the invention block this degradation pathway andincrease the tissue content of these endogenous substances. They may beused in this respect in the prevention and treatment of pathologies inwhich the endogenous cannabinoids, and/or any other substratesmetabolized by the enzyme FAAH, are involved. Examples that may bementioned include the following diseases and complaints:

-   pain, especially acute or chronic pain of neurogenic type: migraine,    neuropathic pain including the forms associated with the herpes    virus and diabetes, acute or chronic pain associated with    inflammatory diseases: arthritis, rheumatoid arthritis,    osteoarthritis, spondylitis, gout, vascularitis, Crohn's disease,    irritable bowel syndrome,-   acute or chronic peripheral pain, vertigo, vomiting, nausea, in    particular post-chemotherapy nausea, eating disorders, in particular    anorexia and cachexia of diverse nature, neurological and    psychiatric pathologies: tremor, dyskinaesia, dystonia, spasticity,    compulsive and obsessive behaviour, Tourette's syndrome, all forms    of depression and anxiety of any nature or origin, mood disorders,    psychoses,-   acute and chronic neurodegenerative diseases: Parkinson's disease,    Alzheimer's disease, senile dementia, Huntington's chorea, lesions    associated with cerebral ischaemia and cranial and medullary trauma,-   epilepsy,-   sleeping disorders, including sleep apnoea,-   cardiovascular diseases, in particular hypertension, cardiac    arrhythmia,-   arteriosclerosis, heart attack, cardiac ischaemia,-   renal ischaemia,-   cancers: benign skin tumours, papillomas and cerebral tumours,    prostate tumours, cerebral tumours (gliobastomas,    medullo-epitheliomas, medullo-blastomas, neuroblastomas, tumours of    embryonic origin, astrocytomas, astroblastomas, ependyomas,    oligodendrogliomas, plexus tumour, neuroepitheliomas, pineal gland    tumours, ependymoblastomas, malignant meningiomas, sarcomatoses,    malignant melanomas, schwennomas),-   immune system disorders, especially autoimmune diseases: psoriasis,    lupus erythematosus, connective tissue diseases, Sjogrer's syndrome,    ankylosing spondylitis, undifferentiated spondylitis, Behcet's    disease, haemolytic autoimmune anaemias, multiple sclerosis,    amyotrophic lateral sclerosis, amylosis, graft rejection, diseases    affecting the plasmocytic line,-   allergic diseases: immediate or delayed hypersensitivity, allergic    rhinitis or allergic conjunctivitis, contact dermatitis,-   parasitic, viral or bacterial infectious diseases: AIDS, meningitis,    inflammatory diseases, especially articular diseases: arthritis,    rheumatoid arthritis, osteoarthritis, spondylitis, gout,    vascularitis, Crohn's disease, irritable bowel syndrome,    osteoporosis, ocular complaints: ocular hypertension, glaucoma,    pulmonary complaints: respiratory pathway diseases, bronchospasms,    coughing, asthma, chronic bronchitis, chronic obstruction of the    respiratory pathways, emphysema,-   gastrointestinal diseases: irritable bowel syndrome, intestinal    inflammatory disorders, ulcers, diarrhoea,-   urinary incontinence and inflammation of the bladder.

The use of the compounds according to the invention, in the form of thebase, or a pharmaceutically acceptable acid-addition salt, hydrate orsolvate, for the preparation of a medicinal product for treating thepathologies mentioned above forms an integral part of the invention.

A subject of the invention is also medicinal products comprising acompound of formula (I), or an acid-addition salt, or alternatively apharmaceutically acceptable hydrate or solvate of the compound offormula (I). These medicinal products find their therapeutic useespecially in the treatment of the pathologies mentioned above.

According to another of its aspects, the present invention relates topharmaceutical compositions containing, as active principal, at leastone compound according to the invention. These pharmaceutical compoundscontain an effective dose of a compound according to the invention, or apharmaceutically acceptable acid-addition salt, hydrate or solvate ofthe said compound, and optionally one or more pharmaceuticallyacceptable excipients.

The said excipients are chosen, according to the pharmaceutical form andthe desired administration form, from the usual excipients known tothose skilled in the art.

In the pharmaceutical compositions of the present invention for oral,sublingual, subcutaneous, intramuscular, intravenous, topical, local,intrathecal, intranasal, transdermal, pulmonary, ocular or rectaladministration, the active principal of formula (I) above, or thepossible acid-addition salt, solvate or hydrate thereof, may beadministered in a unit administration form, as a mixture with standardpharmaceutical excipients, to man and animals for the prophylaxis ortreatment of the above disorders or diseases.

The appropriate unit administration forms comprise oral forms such astablets, soft or hard gel capsules, powders, granules, chewing gums andoral solutions or suspensions, sublingual, buccal, intratracheal,intraocular and intranasal administration forms, forms foradministration by inhalation, subcutaneous, intramuscular or intravenousadministration forms and rectal or vaginal administration forms. Fortopical administration, the compounds according to the invention may beused in creams, ointments or lotions.

By way of example, a unit administration form of a compound according tothe invention in the form of a tablet may comprise the followingcomponents:

Compound according to the invention 50.0 mg Mannitol 223.75 mg Sodiumcroscarmellose 6.0 mg Maize starch 15.0 mg Hydroxypropylmethylcellulose2.25 mg Magnesium stearate 3.0 mg

The said unit forms are dosed to allow a daily administration of from0.01 to 20 mg of active principal per kg of body weight, depending onthe presentation form.

There may be particular cases in which higher or lower doses aresuitable, and such doses also form part of the invention. According tothe usual practice, the dose that is suitable for each patient isdetermined by the doctor according to the mode of administration and theweight and response of the said patient.

According to another of its aspects, the invention also relates to amethod for treating the pathologies mentioned above, which comprises theadministration of an effective dose of a compound according to theinvention, a pharmaceutically acceptable acid-addition salt thereof or asolvate or hydrate of the said compound.

1. A compound corresponding to formula (I)

in which A is a CR₂ group in which R₂ is a hydrogen or fluorine atom ora hydroxyl, cyano, trifluoromethyl, C₁–₆-alkyl or C₁–₆-alkoxy group;when A is a CR₂ group, n is equal to 2 and m is equal to 2; B is acovalent bond or a C₁–₈-alkylene group; R₁ is a group selected fromphenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl,oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, oxadiazolyl,thiadiazolyl, triazolyl, naphthyl, quinolyl, tetrahydroquinolyl,isoquinolyl, tetrahydroisoquinolyl, phthalazinyl, quinazolinyl,quinoxalinyl, naphthyridinyl, cinnolyl, imidazopyrimidinyl,thienopyrimidinyl, benzofuranyl, benzothienyl, benzimidazolyl,benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl,indazolyl, pyrrolopyridyl, furopyridyl, dihydrofuropyridyl,thienopyridyl, dihydrothienopyridyl, imidazopyridyl, pyrazolopyridyl,oxazolopyridyl, isoxazolopyridyl and thiazolopyridyl, said R₁ groupbeing optionally substituted with one or more groups selected from R′and R″; R′ is a halogen atom or a cyano, nitro, hydroxyl, C₁–₆-alkyl,C₁–₆-alkoxy, C₁–₆-thioalkyl, C₁–₆-fluoroalkyl, C₁–₆-fluoroalkoxy,C₁–₆-fluorothioalkyl, C₃–₇-cycloalkyl, C₃–₇-cycloalkyl-C₁–₆-alkylene,azetidinyl, piperidyl, pyrrolidinyl, morpholinyl, piperazinyl, azepinyl,NH₂, NHR₆, NR₆R₇, NR₆COR₇, NR₆SO₂R₇, COR₆, CO₂R₆, SO₂R₆, SO₂NR₆R₇ or—O—(C₁–₆-alkylene)-O— group; R″ is a phenyl, imidazolyl, pyridyl orpyrimidinyl group; each R″ group is optionally substituted with one ormore R′ groups, which may be identical to or different from each other;R₃ is a group of general formula CHR₄CONHR₅ in which: R₄ is a hydrogenatom or a C₁–₆-alkyl group and R₅ is a hydrogen atom or a C₁–₆-alkyl,C₃–₇-cycloalkyl or C₃–₇-cycloalkyl-C₁–₆-alkylene group; and each of R₆and R₇ is, independently, a C₁–₆-alkyl group; in the form of a base, anacid-addition salt, or a solvate.
 2. A compound of formula (I) accordingto claim 1, wherein: B is a covalent bond or a C₁–₄-alkylene group; R₁is a group selected from phenyl, pyridyl, pyridazinyl, pyrimidinyl,pyrazinyl, thiazolyl, quinolyl, isoquinolyl, phthalazinyl, quinazolinyl,quinoxalinyl, naphthyridinyl, furopyridyl, thienopyrimidinyl,imidazopyrimidinyl, benzothiazolyl, benzimidazolyl and benzoxazolyl,said R₁ group being optionally substituted with one or more groupsselected from R′ and R″; R′ is a halogen atom, or a cyano or C₁–₆-alkyl,a C₁–₆-alkoxy, C₁–₆-fluoroalkyl, C₁–₆-fluoroalkoxy, C₃–₇-cycloalkyl,pyrrolidinyl, NH₂, NR₆R₇ or COR₆ group; R″ is phenyl, imidazolyl orpyridyl; each R″ group is optionally substituted with one or more R′groups selected from chlorine and fluorine atoms; R₃ is a group ofgeneral formula CHR₄CONHR₅ in which R₄ is a hydrogen atom or aC₁–₆-alkyl group, and R₅ is a hydrogen atom or a C₁–₆-alkyl,C₃–₇-cycloalkyl or C₃–₇-cycloalkyl-C₁–C₆-alkylene group; and each of R₆and R₇ is, independently, a C₁–₆-alkyl group; in the form of a base, anacid-addition salt, or a solvate.
 3. A compound of formula (I) accordingto claim 1, wherein: A is CH; each of m and n is equal to 2; B is anethyl group; R₁ is selected from phenyl, pyridyl, pyridazinyl,pyrimidinyl, pyrazinyl, thiazolyl, quinolyl, isoquinolyl, phthalazinyl,quinazolinyl, quinoxalinyl, naphthyridinyl, furopyridyl,thienopyrimidinyl, imidazopyrimidinyl, benzothiazolyl, benzimidazolyland benzoxazolyl, said R₁ group being optionally substituted with one ormore groups selected from R′ and R″; R′ represents a halogen atom or acyano or C₁–₆-alkyl, a C₁–₆-alkoxy, C₁–₆-fluoroalkyl, C₁–₆-fluoroalkoxy,C₃–₇-cycloalkyl, pyrrolidinyl, NH₂, NR₆R₇ or COR₆ group; R″ represents aphenyl, imidazolyl or pyridyl; each R″ group is optionally substitutedwith one or more R′ groups selected from chlorine and fluorine atoms; R₃is a group of general formula CH2CONHR₅ in which R₅ is a hydrogen atomor a C₁–C₆-alkyl group; and each of R₆ and R₇ is, independently, aC₁–₆-alkyl group; in the form of the base, an acid-addition salt, or asolvate.
 4. A process for preparing a compound of formula (I) accordingto claim 1, comprising the step of subjecting a carbamate ester ofgeneral formula (Ia)

in which n, m, A, B, R₁ and R₄ are as defined in claim 1 and Rrepresents a methyl or ethyl group, to aminolysis using an amine ofgeneral formula R₅NH₂ in which R₅ is as defined in claim
 1. 5. A processfor preparing a compound of formula (I) according to claim 1, comprisingthe step of subjecting an oxazolidinedione derivative of general formula(V)

in which n, m, A, B, R₁ and R₄ are as defined in claim 1, to aminolysisusing an amine of general formula R₅NH₂ in which R₅ is as defined inclaim
 1. 6. A compound corresponding to the general formula (Ia)

in which A is a CR₂ group in which R₂ is a hydrogen or fluorine atom ora hydroxyl, cyano, trifluoromethyl, C₁–₆-alkyl or C₁–₆-alkoxy group;when A is a CR₂ group, n is equal to 2 and m is equal to 2; B is acovalent bond or a C₁–₈-alkylene group; R₁ is a group selected fromphenyl, pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl,oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, imidazolyl, oxadiazolyl,thiadiazolyl, triazolyl, naphthyl, quinolyl, tetrahydroquinolyl,isoquinolyl, tetrahydroisoquinolyl, phthalazinyl, quinazolinyl,quinoxalinyl, naphthyridinyl, cinnolyl, imidazopyrimidinyl,thienopyrimidinyl, benzofuranyl, benzothienyl, benzimidazolyl,benzoxazolyl, benzisoxazolyl, benzothiazolyl, benzisothiazolyl,indazolyl, pyrrolopyridyl, furopyridyl, dihydrofuropyridyl,thienopyridyl, dihydrothienopyridyl, imidazopyridyl, pyrazolopyridyl,oxazolopyridyl, isoxazolopyridyl and thiazolopyridyl, said R₁ groupbeing optionally substituted with one or more groups selected from R′and R″; R′ is a halogen atom or a cyano, nitro, hydroxyl, C₁–₆-alkyl,C₁–₆-alkoxy, C₁–₆-thioalkyl, C₁–₆-fluoroalkyl, C₁–₆-fluoroalkoxy,C₁–₆-fluorothioalkyl, C₃–₇-cycloalkyl, C₃–₇-cycloalkyl-C₁–₆-alkylene,azetidinyl, piperidyl, pyrrolidinyl, morpholinyl, piperazinyl, azepinyl,NH₂, NHR₆, NR₆R₇, NR₆COR₇, NR₆SO₂R₇, COR₆, CO₂R₆, SO₂R₆, SO₂NR₆R₇ or—O—(C₁–₆-alkylene)-O— group; R″ is a phenyl, imidazolyl, pyridyl,pyrazinyl, pyridazinyl or pyrimidinyl group; each R″ group is optionallysubstituted with one or more R′ groups, which may be identical to ordifferent from each other; R₄ is a hydrogen atom or a C₁–₆-alkyl group;each of R₆ and R₇ is, independently, a C₁–₆-alkyl group; and R is amethyl or ethyl group.
 7. A compound corresponding to the generalformula (V)

in which A is a nitrogen atom or a CR₂ group in which R₂ is a hydrogenor fluorine atom or a hydroxyl, cyano, trifluoromethyl, C₁–₆-alkyl orC₁–₆-alkoxy group; when A is a nitrogen atom, n is an integer equal to 2or 3 and m is 2; when A is a CR₂ group, n is an integer equal to 1, 2 or3 and m is an integer equal to 1 or 2; B is a covalent bond or aC₁–₈-alkylene group; R′ is a group selected from phenyl, pyridyl,pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, oxazolyl, isoxazolyl,thiazolyl, isothiazolyl, imidazolyl, oxadiazolyl, thiadiazolyl,triazolyl, naphihyl, quinolyl, tehahydroquinolyl, isoquinolyl,tetrahydroisoquinolyl, phthalazinyl, quinazolinyl, quinoxalinyl,naphtliyridinyl, cinnolyl, imidazopyrimidinyl, thienopynmidinyl,benzofuranyl, benzothienyl, benzimidazolyl, benzoxazolyl,benzisoxazolyl, benzothiazolyl, benzisothiazolyl, indazolyl,pyrrolopyridyl, furopyridyl, dihydrofuropyridyl, thienopyridyl,dihydrothienopyridyl, imidazopyridyl, pyrazolopyridyl, oxazolopyridyl,isoxazolopyridyl and thiazolopyridyl, said R₁ group being optionallysubstituted with one or more groups selected from R′ and R″; R′ is ahalogen atom or a cyano, nitro, hydroxyl, C₁–₆-alkyl, C₁–₆-alkoxy,C₁–₆-thioalkyl, C₁–₆-fluoroalkyl, C₁–₆-fluoroalkoxy,C₁–₆-fluorothioalkyl, C₃–₇-cycloalkyl, C₃–₇-cycloalkyl-C₁–₆-alkylene,azetidinyl, piperidyl, pyrrolidinyl, morpholinyl, piperazinyl, azepinyl,NH₂, NHR₆, NR₆R₇, NR₆COR₇, NR₆SO₂R₇, COR₆, CO₂R₆, SO₂R₆, SO₂NR₆R₇ or—O-(C₁–₆-alkylene)-O— group; R″ is a phenyl, imidazolyl, pyridyl orpyrimidinyl group; each R″ group is optionally substituted with one ormore R′ groups, which may be identical to or different from each other;R₃ is a group of general formula CHR₄CONHR₅ in which; R₄ is a hydrogenatom or a C₁–₆-alkyl group; and each of R₆ and R₇ is, independently, aC₁–₆-alkyl group; with the proviso that the following compounds areexcluded:3-[1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-piperidyhl]-2,4-oxazolidinedione3-[1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-piperidyhl]-5-methyl-2,4-oxazolidinedione3-[1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-piperidyhl]-5-ethyl-2,4-oxazolidinedione3-[1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-piperidyhl]-5-propyl-2,4-oxazolidinedione3-[1-(4-amino-6,7-dimethoxy-2-quinazolinyl)-4-piperidyhl]—5-(1-methylethyl)-2,4-oxazolidinedione.